Antipsychotic Injectable Depot Composition

ABSTRACT

The present invention is directed to a composition that can be used to deliver an antipsychotic drug such as risperidone, paliperidone or a combination thereof, as an injectable in-situ forming biodegradable implant for extended release providing therapeutic plasma levels from the first day. The composition is in the form of drug suspension on a biodegradable and biocompatible copolymer or copolymers solution using water miscible solvents that is administered in liquid form. Once the composition contacts the body fluids, the polymer matrix hardens retaining the drug, forming a solid or semisolid implant that releases the drug in a continuous manner. Therapeutic plasma levels of the drug can be achieved from the first day up to at least 14 days or more even up to at least four weeks.

CROSS-REFERENCE TO EARLIER FILED APPLICATIONS

The present application claims the benefit of and is a continuation ofapplication Ser. No. 17/577,170 filed Jan. 17, 2022, which is acontinuation of application Ser. No. 16/656,167 filed Oct. 17, 2019, nowU.S. Ser. No. 11/241,377 issued Feb. 8, 2022, which is a continuation ofapplication Ser. No. 16/220,201 filed Dec. 14, 2018, now U.S. Ser. No.10/463,607 issued Nov. 5, 2019, which is a continuation-in-part ofapplication Ser. No. 15/944,894 filed Apr. 4, 2018, now U.S. Ser. No.10/182,982 issued Jan. 22, 2019, which is a divisional of applicationSer. No. 13/690,647 filed Nov. 30, 2012, now U.S. Ser. No. 10/085,936issued Oct. 2, 2018, which is a continuation-in-part of PCT applicationNo. PCT/EP2011/059000, filed May 31, 2011, which claims the benefit ofEP 10382154.2 filed May 31, 2010, and said application Ser. No.16/220,201 filed Dec. 14, 2018, is a continuation-in-part of applicationSer. No. 16/032,270 filed Jul. 11, 2018, now U.S. Ser. No. 10/195,138issued Feb. 5, 2019, which is a continuation-in-part of application Ser.No. 13/690,707 filed Nov. 30, 2012, now U.S. Ser. No. 10/058,504 issuedAug. 29, 2018, which is a continuation-in-part of PCT application No.PCT/EP2011/059001, filed May 31, 2011, which claims the benefit of EP10382153.4 filed May 31, 2010, the entire disclosures of which arehereby incorporated by reference.

FIELD OF THE INVENTION

The present invention relates to implantable compositions that formextended drug-delivery devices comprising certain atypical antipsychoticdrugs, particularly risperidone. Specifically, the present invention isrelated to compositions for injectable in-situ forming biodegradableimplants comprising risperidone.

BACKGROUND OF THE INVENTION

Risperidone is an atypical antipsychotic drug with benzisoxazole andpiperidine functional groups. It acts as a strong dopaminergicantagonist and selective serotonin receptor antagonist. Risperidone isFDA approved for the treatment of schizophrenia since 1993. It is theonly drug presently approved for the treatment of schizophrenia in youngpeople under 18 years, and together with lithium, for the treatment ofbipolar disorders in children/youth ages between 10-18 years old.Conventional risperidone therapy of schizophrenia involves daily oraltablets, although it is also available as a solution and orallydisintegrating tablets.

In fact, one of the intrinsic problems that risperidone-targetedpatients usually face is the dissociation (non-compliance) of someschizophrenic patients from the treatment, especially when it therapyconsists of a daily dosing, leading to irregular or inconstanttreatments and thereby promoting the occurrence of psychotic episodesand crisis. Moreover, this kind of therapy gives rise to highfluctuations in plasma levels (measured as the difference between Cmaxand Cmin) in patients, thereby usually affecting the patient's mood.

Risperidone is, therefore, a good drug candidate for incorporation intosustained delivery devices, where the patients would be covered ortreated for long time periods with just one dose and without the need ofcaregivers to pay attention to a daily administration, and where a morehomogeneous or level plasma concentration in the patient is desirable.

One of the most usual ways to administer risperidone presently isthrough the use of depot injections. Depot injections allow carefulcontrol of drug usage (as opposed to orally administered drugs) andensure regular contact between the caregivers team and the patient,where overall treatment efficacy and/or side effects may be identified.Furthermore, it is easy to identify non-compliant patients and prepareinterventions. However, in situ forming implants currently described inthe state of the art cannot properly control risperidone release fromthe implant and fail to allow obtaining therapeutic plasma levels in abi-weekly administration protocol, with reasonable differences betweenmaximum and minimum concentrations.

Currently, the long-acting injectable risperidone formulation, RisperdalConsta®, is the first depot dosage form with an atypical antipsychoticdrug in the market. It is an intramuscular risperidone-containing PLGAmicroparticle formulation, and it is intended to deliver therapeuticlevels of risperidone suitable for bi-weekly administration. However,due to the inherent lag phase of most microparticle based products, thepatient is required to supplement the first weeks with daily doses oforal risperidone after first administration. Approximately three weeksafter a single intramuscular injection of Risperdal Consta® andconcurrent daily doses of oral risperidone, the microspheres releasesufficient risperidone in the systemic circulation that the patient candiscontinue supplementation with daily doses of the oral therapy.However, this period of oral supplementation presents a risk factor fornon-compliance. Also, the presence in the body of two doses at the sametime could present a potential risk of adverse events, such as irregularformulation behavior and toxicity (occurrence of unwanted side effects).

The compositions and devices of the invention, on the contrary, canevoke therapeutic drug plasma levels from the first day and for at least14 days, avoiding the need of supplementary oral daily therapy from theadministration moment. These compositions can also reduce thedifferences between Cmax and Cmin as observed with daily-administeredoral tablets and subsequently may reduce variations in the patient mood.In addition, they can also cover a period within administrations that isat least as long as the period covered by currently marketedextended-release risperidone formulations.

The compositions of the invention are based on a biodegradable copolymerpoly(L-lactide-co-glycolide) matrix. These polymers have been used formany years in medical applications like sutures described in U.S. Pat.No. 3,636,956 by Schneider, surgical clips and staples described in U.S.Pat. No. 4,523,591 by Kaplan et al., and drug delivery systems describedin U.S. Pat. No. 3,773,919 by Boswell et al. However, most of theexisting formulations using these biodegradable polymers requiremanufacturing of an implantable device in solid form prior to theadministration into the body, which device is then inserted through anincision or is suspended in a vehicle and then injected. In suchinstances, the drug is incorporated into the polymer and the mixture isshaped into a certain form such as a cylinder, disc, or fiber forimplantation. With such solid implants, the drug delivery system has tobe inserted into the body through an incision. These incisions aresometimes larger than desired by the medical profession and occasionallylead to a reluctance of the patients to accepts such an implant or drugdelivery system.

U.S. Pat. No. 8,221,778 to Siegel et al. (corresponding to WO2005/070332) discloses an implant containing risperidone (10-60% wt) andPLGA (90-40% wt) having a lactic acid to glycolic acid ratio of 50:50 to100:0. These implants are not formed in situ.

Injectable biodegradable polymeric matrix implants based on lactic acid,glycolic acid and/or their copolymers for sustained release have alreadybeen described in the art. U.S. Pat. No. 5,620,700 issued to Berggrendescribes a bioerodible oligomer or polymer material containing drug forlocal application into a diseased tissue pocket such as a periodontalpocket. However, the material requires heating to high temperatures tobecome sufficiently flowable to allow the injection, so that hardeningof the material after cooling to the body temperature forms the implant.

U.S. Pat. No. 6,143,314 to Chandrashekar discloses an injectablecomposition that forms an implant in situ. The composition is made ofdrug, organic solvent and a PLGA/PEG block copolymer.

U.S. Pat. No. 6,673,767 issued to Brodbeck describes procedures for insitu formation of biodegradable implants by using biocompatible polymersand biocompatible low water-miscible solvents. A viscous polymericsolution containing the drug that upon injection releases the drug in acontrolled manner is obtained through the use of low water-solublesolvents. Solvents with low water-solubility (less than 7% miscibilityin water) are used as a method to reduce the release of the drug inaqueous mediums, allowing initial drug releases of 10% or lower duringthe first 24 hours. However, in our experience, the use ofwater-immiscible and/or low water-miscible solvents cannotsatisfactorily control the initial in vivo release of risperidone duringthe first 24 hours. For example, the use of benzyl alcohol, a solventspecifically disclosed in U.S. Pat. No. 6,673,767, causes very highplasma levels of risperidone in the first 3 days and then the plasmalevels decrease to very low levels in 7 days.

U.S. Pat. No. 6,331,311 issued to Brodbeck also discloses injectabledepot compositions comprising a biocompatible polymer such as PLGA, asolvent such as N-methyl-2-pyrrolidone and a beneficial agent such as adrug, further comprising an emulsifying agent such as polyols. However,the compositions disclosed do not perform satisfactorily when thebeneficial agent is risperidone, because the use of a two-phasecomposition with emulsifying agents accelerates implant hydration andincreases effective releasing surface area, impairing the control on theinitial burst release and causing a fast decrease in drug release fromthe first days to the following ones. For example, a comparatorcomposition was prepared according to the '311 patent. A containercontaining risperidone (150 mg), PLGA (300 mg, having an inherentviscosity of 0.32 dl/g and irradiated by R-irradiation to a dose of 25KGy) and NMP (700 mg) was prepared. Another container containingpolyvinyl alcohol in water (1 ml of a 2% wt/v). The contents of thecontainers were mixed, then the mixture was transferred to a syringe andinjected intramuscularly (an amount equivalent to 2.5 mg risperidone)into the gluteus of New Zealand White rabbits (n=3). More than 70% ofthe total AUC of active moiety was released within the first 5 daysafter the injection. Such a formulation is unable to provide therapeuticplasma levels of risperidone for a period of at least two weeks.

U.S. Pat. No. 4,938,763, issued to Dunn et al., discloses a method foran injectable in situ forming implant. A biodegradable polymer orcopolymer dissolved in a water-miscible solvent with a biologicallyactive agent either is dissolved or dispersed within the polymericsolution. Once the polymeric solution is exposed to body fluids, thesolvent diffuses, and the polymer solidifies thereby entrapping the drugwithin the polymer matrix. Even though Dunn et al. discloses the use ofwater miscible solvents for obtaining in situ forming polymericimplants, it discloses a number of polymers and solvents and evenproportions between the different ingredients that do not produce asatisfactory implant with the appropriate release characteristics,particularly when the implant contains risperidone as active principle.For example, a comparator composition was prepared according to the '763patent. A container containing risperidone (50 mg) and PLGA (784 mg,monomer ratio of lactic acid to glycolic acid monomer of 75:25) andhaving an inherent viscosity of 0.20 dl/g was prepared. Anothercontainer containing NMP (1666 mg) was prepared. The contents of thecontainers were mixed. Then the mixture was transferred to a syringe anda portion (1250 mg, corresponding to 25 mg of risperidone) was injectedinto an aqueous liquid to determine its in vitro release profile. Morethan 50% of the risperidone was released within the first 2 days. Such aformulation is unable to provide therapeutic plasma levels ofrisperidone for a period of at least two weeks.

Another way to avoid surgery to administer these drugs is the injectionof small-sized polymeric particles, microspheres or microparticlescontaining the respective drug. U.S. Pat. Nos. 4,389,330 and 4,530,840describe a method for the preparation of biodegradable microparticles.U.S. Pat. Nos. 5,688,801 and 6,803,055 disclose microencapsulation of1,2-benzazoles into polymeric particles to achieve a drug release overextended periods of time in the treatment of mental disorders. Thesemicroparticles require resuspension into aqueous solvents prior to theinjection. These formulations do not form a single (nonparticulate)solid implant.

U.S. Pat. No. 5,770,231 describes a method for producing biodegradablemicroparticles for sustained release of risperidone and9-hydroxy-risperidone by dissolving the drug within an organic phase.However, the use of organic solvents that are able to dissolve therisperidone mostly or completely gives rise to very high initial plasmalevels of risperidone, after implantation of the particles, due to thediffusion of the drug along with the diffusion of the solvent.

U.S. Pat. No. 7,118,763 describes two methods of making multi-phasesustained-release microparticle formulations based on the combination ofdifferent particle sizes or microparticles exhibiting different releaseprofiles. The combination of two different release profiles allows therelease of the drug for periods longer than two weeks. However, inpractice this combination requires a mixture of particles from at leasttwo different batches, involving the multiplication of end productspecifications and increasing batch-to-batch variability.

WO 2008/153611 A2 discloses numerous sustained delivery systems ofrisperidone and a metabolite. Risperidone is mixed with a solublethermoplastic polymer, forming an encapsulating residue upon injectionfrom which risperidone is slowly released. However, the authors failedto recognize the influence of process parameters and of specific resulteffective variables on the initial risperidone burst. In particular,none of the formulations contained a risperidone/polymer mass ratiobetween 25 and 35%, as in the presently claimed formulations. Moreover,all the tests disclosed therein were carried out using a specificsolvent, namely N-methyl-2-pyrrolidone (NMP).

In addition, although microparticle formulations can be administered byinjection, they cannot always satisfy the demand for a biodegradableimplant because they sometimes present difficulties in the large-scaleproduction. Moreover, in case of any medical complication afterinjection, they are more difficult to remove from the body thanimplantable compositions such as those of the invention, which form asingle body.

The art also discloses sustained-release delivery devices comprising adrug, PLGA as polymer and a water-miscible solvent such asn-methyl-pyrrolidone (NMP) or dimethyl sulfoxide (DMSO). However, inpractice the experiments disclosed nearly in every case use NMP assolvent (WO 2004081196, WO 2001035929, WO 2008153611) or need differentadditives to control the initial burst (WO 2000024374, WO 2002038185,WO2008100576).

Therefore, the compositions already described in the state of the artfail to provide suitable extended release risperidone compositions, kitsand treatments for psychiatric disorders. In summary, there still existsa need of compositions and devices for sustained-released deliverysystems providing a controlled, constant release of the drug from thevery first day, avoiding irregular initial bursts, and showingcontrolled release profile during prolonged periods of time.

SUMMARY OF THE INVENTION

The present invention seeks to overcome one or more of the disadvantagesof known depot formulations containing an atypical anti-psychotic.Contrary to known injectable depot compositions, the compositions of theinvention provide an easier method for the production of a single unitimplantable device allowing constant and effective plasma levels duringa period comprising from the first day up to at least 14 days or atleast up to 4 weeks. The compositions of the invention are injected as aliquid or semisolid formulation that precipitates by solvent diffusionafter injection into a subject and forms a single (not multiparticulate)solid implant at an injection site. The compositions of the presentinvention provide an easier method for the production of an implant orsingle unit implantable device allowing constant and effective plasmalevels during a dosing period comprising from the first day up to atleast 14 days after administration, while avoiding irregular initialburst release of the drug. The compositions of the present inventionexhibit satisfactory initial and continuous release profiles using DMSOas solvent and without the need of any additional additive to controlthe initial burst of the composition. By using DMSO as the solvent, theimplant provides a smaller initial plasma level of drug than otherinjectable formulations and therefore provides a better control of therelease of the drug during the first 5 days after the injection.

The risperidone-containing compositions of the invention providetherapeutic drug plasma levels from the first day up to at least 14 daysafter implantation, thereby avoiding the need for supplementary oraldaily therapy within one day of the time of administration. Thesecompositions can also reduce the fluctuations between Cmax and Cmin,especially as compared to those observed with daily administration oforal tablets, and subsequently may reduce variations in the patient moodcaused by excessive plasma level fluctuations. In addition, they canalso cover a dosing period that is at least as long as the dosingperiods covered by currently marketed extended-releaserisperidone-containing formulations.

Some of the key points where the compositions of the invention showimprovements over the state of the art include:

-   -   Stability, by using a solid product for reconstitution previous        to injection;    -   Pharmacokinetic profile:        -   Onset: The compositions of the invention provide therapeutic            plasma levels from the first day after administration,            avoiding the 2-3 weeks lag time that the currently marketed            long-term risperidone-containing product shows.        -   Duration: The compositions of the invention may allow an            increase in the interval between administrations, meaning an            increase in the dosing period, as compared to currently            marketed long-term risperidone-containing product.    -   Plasma levels: The compositions of the invention provide more        even sustained plasma levels, and with lower differences between        Cmax and Cmin than the currently marketed long-term        risperidone-containing product.

The present inventors have identified that the initial burst release ofthe drug can be satisfactorily controlled during at least 2 weeks bycontrolling at least one of the following factors, either alone or incombination:

-   -   the viscosity of the polymeric solution;    -   the risperidone/polymer mass ratio in the implant;    -   the risperidone particle size;    -   the polymeric solution/drug mass ratio; and    -   the solvent/risperidone mass ratio.

It should be noted that there was little recognition if any in the artthat the above-enumerated variables would be result effective in termsof their impact upon the initial release of risperidone afterimplantation or after placement in an aqueous fluid. By adequatelycontrolling at least some of these result effective variables, releaseof drug from the implant during at least the first two weeks can beprecisely controlled, allowing satisfactorily controlled releaseprofiles from the very first day until at least 14 days, and achievingin most cases dosing periods of more than 21 days or more than 30 daysand up to 40 days or up to six months following administration of asingle dose within a dosing period.

The invention provides injectable compositions and corresponding kits inwhich a solid polymer or copolymer is dissolved in a solvent, which isnon-toxic and water miscible, to form a liquid polymeric solution, whichis mixed with risperidone. When these compositions are exposed to bodyfluids or water, the solvent diffuses away from the polymer-drug mixtureand water diffuses into the mixture where it coagulates the polymerthereby trapping or encapsulating the drug within the polymeric matrixas the implant solidifies into a single body. The release of the drugthen follows the general characteristics for diffusion or dissolution ofa drug from within a polymeric matrix. Drug is also released by polymererosion/degradation. The risperidone forms a suspension or dispersionwithin a biodegradable and biocompatible polymeric solution to form aninjectable composition that can be administered by means of a syringeand a needle. The composition solidifies inside the body by solventdiffusion, thereby forming the single implant at the site of injection.

One aspect of the invention provides an injectable composition asdescribed and/or exemplified herein. The compositions of the inventioncomprise at least a polymer matrix, a solvent for the polymer and adrug, wherein the composition is defined by certain selected ranges andratios of at least one of the following parameters, either alone or incombination:

-   -   the viscosity of the polymeric solution (polymer+solvent) or        injectable composition;    -   the risperidone/polymer mass ratio; and/or    -   the risperidone particle size.

Additional parameters such as the mass ratio between the amounts ofpolymeric solution (polymer+solvent) and drug, and the solvent/drug massratio, can also be useful to provide control over the initial release ofrisperidone from the compositions of the invention.

A first aspect of the invention provides an injectable depotcomposition, comprising:

-   -   a. a drug, such as is risperidone and/or its metabolites or        prodrugs in any combination thereof;    -   b. at least a biocompatible polymer which is a copolymer        comprising lactic acid and glycolic acid monomers, wherein the        monomers are present at a monomer ratio of lactic to glycolic        acid in the range from about 48:52 to about 77:23, and    -   c. at least a water-miscible solvent with a dipole moment about        3.9-4.3 D,        wherein the solvent and polymer form a polymer solution having a        viscosity in the range of 0.5 to 3.0 Pa·s, and the solvent/drug        mass ratio ranges from about 10:1 to about 4:1, characterised in        that the drug/polymer mass ratio is between 25 and 35% expressed        as the weight percentage of the drug with respect of the drug        plus polymer.

Embodiments of the invention include those wherein the drug is presentin freebase form, in salt form or a mixture thereof.

In some embodiments, the concentration of the polymeric component in theinjectable composition is in the range of about 25-50%, (expressed asthe percentage of polymer weight based on total polymeric solutioncomponent) and or about 30-40%.

In some embodiments, the injectable composition has a viscosity in therange of about 0.5-7.0 Pa·s, more preferably about 0.5-3.0 Pa·s, andmost preferably about 0.7-3.0 Pa·s.

In some embodiments, the concentration of drug in the injectablecomposition is generally in the range of about 4 to about 16% wt,expressed as the percentage of the drug with respect to the totalcomposition weight.

In some embodiments, the compositions of the invention comprise abiodegradable poly(L-lactide-co-glycolide) copolymer (PLGA) matrix. Themonomer ratio of lactic acid to glycolic acid monomers present in thepolymer can range from about 45:55 to about 75:25, about 50:50 to about75:25, about 50:50 to about 70:30, about 50:50 to about 65:35, or about65:35 to about 75:25. In some embodiments, the intrinsic or inherentviscosity of the polymer is in the range of about 0.16 to about 0.60dl/g when measured in chloroform at 25° C. and a 0.1% (wt/v)concentration. In some embodiments, the PLGA copolymer is end-capped. Insome embodiments, the PLGA copolymer is irradiated with beta-radiationprior to inclusion in the injectable composition. In some embodiments, acommercially available PLGA copolymer has an initial intrinsic viscositythat is to high for use but after irradiation with beta-radiation it hasan intrinsic viscosity that is within the ranges specified hereinthereby rendering it suitable for use in the injectable composition.

The use of a solvent having a dipole moment in the range of about3.9-4.3 D results in an implant that provides suitable initial plasmalevels of risperidone and therefore a better control of the release ofthe drug during the first 5 days after the injection. This solventeffect on the release of risperidone is completely unexpected.Embodiments of the invention include those wherein the solvent isselected from the group consisting of DMSO, NMP, PEG or a combinationthereof.

The invention also provides an injectable composition that forms asingle solid body implant in a subject to which it is administered, thecomposition comprising:

-   -   a. a polymeric solution comprising a biodegradable        poly(L-lactide-co-glycolide) polymer having a monomer ratio of        lactic acid to glycolic acid in the range of 50:50 to 75:25, and        a solvent having a dipole moment in the range of 3.9-4.3 D,        wherein the solvent is present in an amount sufficient to        dissolve the polymer; and    -   b. drug-containing particles of risperidone, a metabolite of        risperidone, a prodrug of risperidone or a combination thereof        at least partially dispersed in the polymeric solution, the        particles having a size distribution as follows: not more than        10% of the total volume of drug particles is less than 10        microns in size, not more than 10% of the total volume of drug        particles is greater than 225 microns in size, and the d0.5 of        the size distribution is in the range of about 60-130 microns;        wherein    -   c. the intrinsic or inherent viscosity of the polymer is in the        range of about 0.16 to about 0.60 dl/g when measured in        chloroform at 25° C. and a 0.1% concentration;    -   d. the viscosity of the polymeric solution is in the range of        about 0.5-7.0 Pa·s;    -   e. the concentration of drug in the injectable composition is in        the range of about 4 and 16 wt %, expressed as the percentage of        the drug with respect to the total composition weight, or the        mass ratio of the amount of polymeric solution (polymer+solvent)        to the amount of drug in the injectable composition ranges from        about 15:1 to 5:1;    -   f. the concentration of polymer in the injectable composition is        in the range of about 25-50% expressed as the percentage of        polymer weight based on total polymeric solution component; and    -   g. the composition has a solvent/drug mass ratio ranging from        about 10:1 to about 4:1.

In some embodiments, the composition is injectable by hand through a 18to 22 gauge needle, and preferably through a 20-21 gauge needle.

Another aspect of the invention provides a pharmaceutical kit suitablefor preparation of an injectable composition that forms a biodegradablenon-particulate solid implant in situ in a subject in need thereof, thekit comprising: a first container comprising risperidone (and/ormetabolite thereof and/or prodrug thereof having a water solubility lessthan or about 2 mg/ml in water-miscible solvent such as DMSO) and abiocompatible polymer having an inherent viscosity in the range of about0.20-0.50 dl/g or about 0.20-0.48 dl/g, and a second containercomprising a water-miscible solvent in which the biocompatible polymeris soluble, whereby mixing of the contents of the first container withthe contents of the second container affects formation of an injectablepolymer solution composition as described herein having a viscosity inthe range of about 0.50 and 4.0 Pa·s. In some embodiments, thecontainers are syringes and the mixing of the contents of the first andsecond containers may be performed by direct or indirect connectionfollowed by moving forwards and backwards the plungers of the syringes.

Embodiments of the invention include those wherein: a) the risperidoneis present in solid form in the container prior to mixing with thesolvent; b) the risperidone is present in particulate form or as alyophilisate in the container prior to mixing with the solvent; c) theparticle size distribution of the risperidone is as follows: not morethan 10% of the total volume of drug particles are less than 10 micronsin size and not more than 10% of the total volume of drug particles aregreater than 225 microns in size; d) the d0.5 of the particle sizedistribution is in the range of about 60-130 microns; e) the mass ratioof the amount of polymeric solution (polymer+solvent) and to the amountof risperidone in the injectable composition ranges from about 15:1 to5:1; f) the mass ratio of the amount of solvent and the amount ofrisperidone (mg solvent/mg risperidone) in the injectable compositionranges from about 12:1 to 4:1; g) the kit further comprises an alkalineagent; h) the mole ratio of risperidone to alkaline agent ranges from2/3 to 2/5; i) the solvent, polymeric solution, risperidone and/orinjectable composition is sterilized prior to administration; and/or j)the kit further comprises an alkaline agent in either or bothcontainers.

Another aspect of the invention provides a method for preparing aninjectable composition as described herein. In some embodiments, themethod comprises:

-   -   a. subjecting a biodegradable poly(L-lactide-co-glycolide)        polymer, having a monomer ratio of lactic acid to glycolic acid        in the range of 50:50 to 75:25 and having a first molecular        weight, to a sufficient amount of β-irradiation to degrade at        least a portion of the polymer thereby reducing its molecular        weight and reducing the intrinsic viscosity of the polymer;        and b) mixing the polymer with a solvent to form a polymeric        solution, wherein the properties of the polymeric solution are        as described herein; and wherein drug is included with the        polymer or solvent prior to mixing or wherein drug is added to        the polymeric solution after formation thereof, thereby forming        the injectable composition.

In some embodiments, the invention provides a process for preparing aninjectable composition, comprising: a) dissolving a polymer having amolecular weight greater than about 15 KDa in a solvent having a dipolemoment about 3.9-4.3 D to form a polymeric solution having a viscositygreater than about 0.5 Pa·s, wherein the concentration of the polymer inthe solution is in the range of about 25-50%, expressed as thepercentage of polymer weight based on total solution weight, wherein thepolymer comprises lactic acid and glycolic acid monomers, wherein themonomers are present at a monomer ratio of lactic acid to glycolic acidin the range of about 50:50 to 75:25; and b) subjecting the polymer toat least 5 KGy or at least 10 KGy or about 5 to about 25 KGy or about 10to about 25 KGy of 3-irradiation to degrade at least a portion of thepolymer thereby reducing its molecular weight to a range of about 25-52KDa and reducing the viscosity of a respective polymeric solutionthereof to a range of about 0.5 to 3.0 Pa·s or about 0.5 to 4.0 Pa·s. Insome embodiments, drug is included in the polymeric solution, and theweight percentage of drug with respect to the total weight of drug pluspolymer is in the range of about 25 to 35%.

Another aspect of the invention provides the use of an injectable depotcomposition as described herein for the treatment of schizophrenia orbipolar disorders in the human body. The method comprises administeringto a subject in need thereof an amount of injectable depot compositionas described herein sufficient to provide a therapeutic dose ofrisperidone for a period of at least two weeks following administrationthereof.

Embodiments of the invention include those wherein: a) the compositionis administered every two weeks, every three weeks, every four weeks orevery five weeks during a treatment period; b) the composition providesa therapeutic plasma level of risperidone or other form thereof fromwithin 24 hours after administration to at least 14 days afteradministration; c) the plasma level of active moiety ranges from about 5to about 150 ng/ml and preferably from about 10 to about 100 ng/ml inthe steady state during a dosing period; d) the implant provides anactive moiety (risperidone+9-OH risperidone) plasma level within therange of about 5 to about 80 ng/ml when about 116 to about 700 mg,respectively, of the composition comprising about 25 to about 150 mg,respectively, of risperidone are administered via injection; e) theinjectable composition is exposed to an aqueous fluid thereby forming asolid body which is then administered to a subject in need thereof; f)the injectable composition is formed within one month, within threeweeks, within two weeks, within one week, within three days, within oneday, within less than one day, within 18 hours, within 12 hours, within6 hours, within 1 hour, within 15 minutes or within 5 minutes prior toadministration to a subject; g) the injectable composition is warmed orcooled prior to administration to a subject; h) the polymer, solvent,polymer solution and/or drug is sterilized prior to administration; i)sterilization comprises sterilization of the drug or polymer by exposureto beta-irradiation in the range 5-25 KGy; j) sterilization comprisessterilization of the polymer solution by filtration through a filtrationmedium having a nominal pore size of 22 microns or less; and/or k) thecomposition is administered intramuscularly, intraperitoneally,intrathecally, intravaginally, subcutaneously, intracranially orintracerebrally. In some embodiments, the preferred mode ofadministration is intramuscular.

The specification discloses one or more embodiments that incorporatefeatures of this invention. The scope of the present invention is notlimited solely to the disclosed embodiments. The invention includes allcombinations and sub-combinations of the various aspects and embodimentsdisclosed herein. These and other aspects of this invention will beapparent upon reference to the following detailed description, examples,claims and attached figures.

BRIEF DESCRIPTION OF THE FIGURES

The accompanying drawings, which are incorporated herein and form a partof the specification, illustrate one or more embodiments of the presentinvention and, together with the description, further serve to explainthe principles of the present invention and to enable a person skill inthe pertinent art to make and use the invention. The following drawingsare given by way of illustration only, and thus are not intended tolimit the complete scope of the present invention.

FIG. 1: In vitro release profile of risperidone for the composition ofComparative Example 1 (risperidone, polymer and a water-insolublesolvent).

FIG. 2: In vivo plasma levels of risperidone plus 9-OH-risperidonefollowing injection of the composition of Comparative Example 1(risperidone, polymer and a water-insoluble solvent) in rabbits.

FIG. 3: In vitro release profile of risperidone for the composition ofExample 1 (risperidone, polymer and water-soluble solvents havingdifferent dipole moment).

FIG. 4: In vitro release profile of risperidone for the composition ofExample 2 (risperidone, polymer and a water-soluble solvent having ahigh solubility for risperidone).

FIG. 5: In vivo plasma levels of risperidone plus 9-OH-risperidonefollowing injection of the composition of Example 2 (risperidone,polymer and a water-soluble solvent having a high solubility forrisperidone) in rabbits.

FIG. 6: In vitro release profile of risperidone for the composition ofExample 3 (risperidone, polymer and water-soluble solvents havingmoderate to low solubility for risperidone).

FIG. 7: In vitro release profile of risperidone for the compositions ofExample 4 (different polymer concentrations with respect to solvent,DMSO).

FIG. 8: In vitro release profile of risperidone for the compositions ofExample 5 (low polymer concentration of a solvent having a highsolubility for risperidone).

FIG. 9: In vivo plasma levels of risperidone plus 9-OH-risperidonefollowing injection of the composition of Example 5 (low polymerconcentration of a solvent having a high solubility for risperidone) inrabbits.

FIG. 10: In vivo plasma levels of risperidone plus 9-OH-risperidonefollowing injection of the composition of Example 6 (intermediatepolymer concentration with respect to solvent) in rabbits.

FIG. 11: In vivo plasma levels of risperidone plus 9-OH-risperidonefollowing injection of the compositions of Example 7 (different drugloadings) in rabbits.

FIG. 12: In vitro release profile of risperidone for Composition B ofExample 8 (different particle sizes).

FIG. 13: In vivo plasma levels of risperidone plus 9-OH-risperidonefollowing injection of Composition A of Example 8 (different particlesizes) in rabbits.

FIG. 14: In vivo plasma levels of risperidone plus 9-OH-risperidonefollowing injection of Composition B of Example 8 (different particlesizes) in rabbits.

FIG. 15: In vivo plasma levels of risperidone plus 9-OH-risperidonefollowing injection of Composition B of Example 8 (different particlesizes) in dogs.

FIG. 16: In vitro release profile of risperidone for the compositions ofExample 9 (different viscosities of the polymeric solution).

FIG. 17: In vivo plasma levels of risperidone plus 9-OH-risperidonefollowing injection of the compositions of Example 9 (differentviscosities of the polymeric solution) in rabbits.

FIG. 18: In vivo plasma levels of risperidone plus 9-OH-risperidonefollowing injection of the compositions of Example 9 (differentviscosities of the polymeric solution) in rabbits.

FIG. 19: In vivo plasma levels of risperidone plus 9-OH-risperidonefollowing injection of the compositions of Example 9 (differentviscosities of the polymeric solution) in rabbits.

FIG. 20: In vitro release profile of risperidone for the compositions ofExample 10 (different drug/polymer mass ratios in DMSO as solvent).

FIG. 21: In vivo plasma levels of risperidone plus 9-OH-risperidonefollowing injection of the compositions Example 10 (differentdrug/polymer mass ratios) in rabbits.

FIG. 22: In vivo plasma levels of risperidone plus 9-OH-risperidonefollowing injection of the compositions Example 10 (differentdrug/polymer mass ratios) in rabbits.

FIG. 23: In vivo plasma levels of risperidone plus 9-OH-risperidonefollowing injection of the compositions Example 10 (differentdrug/polymer mass ratios) in dogs.

FIG. 24: In vivo plasma levels of risperidone plus 9-OH-risperidonefollowing injection of the compositions Example 11 (different polymericsolution/drug mass ratios) in rabbits.

FIG. 25: In vivo plasma levels of risperidone plus 9-OH-risperidonefollowing injection of the compositions Example 12 (differentsolvent/drug mass ratios) in rabbits.

FIG. 26: In vivo plasma levels of risperidone plus 9-OH-risperidonefollowing injection of the compositions Example 13 (optional addition ofMg(OH)₂) in rabbits.

FIG. 27: In vitro release profile of risperidone for the compositions ofExample 14 (different reconstitution methods).

FIG. 28: In vivo plasma levels of risperidone plus 9-OH-risperidonefollowing injection of the compositions of Example 14 (differentreconstitution methods) in rabbits.

FIG. 29: In vivo plasma levels of risperidone plus 9-OH-risperidonefollowing injection of the compositions of Example 14 (differentreconstitution methods) in dogs.

FIG. 30: In vitro release profile of risperidone for the compositions ofExample 15 (sterilization by irradiation).

FIG. 31: In vitro release profile of risperidone for the compositions ofExample 15 (sterilization by irradiation).

FIG. 32: In vivo plasma levels of risperidone plus 9-OH-risperidonefollowing injection of the compositions of Example 15 (sterilization byirradiation) in rabbits.

FIG. 33: In vivo plasma levels of risperidone plus 9-OH-risperidonefollowing injection of the compositions of Example 15 (sterilization byirradiation) in rabbits.

FIG. 34: In vivo plasma levels of risperidone plus 9-OH-risperidonefollowing injection of the compositions of Comparative Example 2(compositions obtained through the procedures of the prior art) in dogs.

FIG. 35 depicts an exemplary kit comprising syringes connected through aconnector device.

FIG. 36 depicts another exemplary kit comprising syringes connectedthrough a direct thread.

DETAILED DESCRIPTION OF THE INVENTION

As used herein and unless otherwise specified, the term “risperidone”refers to“4-[2-[4-(6-fluorobenzo[d]isoxazol-3-yl)-1-piperidyl]ethyl]-3-methyl-2,6-diazabicyclo[4.4.0]deca-1,3-dien-5-one”and to the salt, freebase, amorphous, crystalline, anhydrous, hydrate,optically pure, optically enriched or racemic forms thereof.Combinations of these various forms are also within the scope of theinvention. The compositions of the invention can comprise risperidone, ametabolite thereof, e.g. paliperidone which is also known as“(RS)-3-[2-[4-(6-fluorobenzo[d]isoxazol-3-yl)-1-piperidyl]ethyl]-7-hydroxy-4-methyl-1,5-diazabicyclo[4.4.0]deca-3,5-dien-2-one”, a prodrug thereof, a derivative thereof or acombination thereof.

Suitable pharmaceutically acceptable salts of risperidone, or ametabolite or derivative thereof, include the acid addition salts withhydrochloric acid, methane sulfonic acid, benzene sulfonic acid,tartaric acid, maleic acid, malic acid, ethane disulfonic acid, lacticacid, acetic acid, and mandelic acid. Exemplary salts includerisperidone dihydrochloride, risperidone mesylate, risperidonehemitartrate, risperidone hydrogenmaleate, risperidone (L)-hemimalate,risperidone hemiedisylate, risperidone (L)-lactate, risperidone acetatemonohydrate, and risperidone (R)-mandelate. Such salts can be preparedaccording to U.S. Publication No. 20040266791, the relevant disclosureof which is hereby incorporated by reference. Preferred prodrugs andsalts of risperidone or paliperidone include those having a watersolubility of less than or about 2 mg/ml. In some embodiments,risperidone, its metabolite and/or its derivative is present as afreebase in the injectable composition.

As used herein, the term “prodrug” is taken to mean a compound that isadministered in an inactive (or less than fully active) form, and issubsequently converted to an active pharmacological agent through normalmetabolic processes. A prodrug serves as a type of ‘precursor’ to theintended drug, e.g. risperidone. Exemplary prodrugs include the fattyacid esters of paliperidone (9-hydroxyrisperidone) as disclosed in U.S.Pat. No. 6,555,544, the entire disclosure of which is herebyincorporated by reference. Preferred prodrugs and salts of paliperidoneinclude those having a water solubility of less than or about 2 mg/ml.

As used herein, the term “derivative” is taken to mean a compound thatis obtained by chemical modification of a parent compound such that the“derivative” includes within it almost all or all of the chemicalstructure of the parent (or base) compound. A derivative is a compoundthat is formed from a similar compound or a compound that can beimagined to arise from another compound, if one atom is replaced withanother atom or group of atoms. A derivative is a compound derived orobtained from another and containing essential elements of the parentsubstance. A derivative is a chemical compound that may be produced fromanother compound of similar structure in one or more steps.

As used herein, the term “polymeric solution” is taken to mean the fluidcomposition comprising a combination of the solvent and the polymerdissolved therein. In some embodiments, at least 80%, at least 90%, atleast 95%, at least 99% or all of the polymer is dissolved in thesolvent. If not otherwise specified, the viscosity value of thepolymeric solution or the injectable composition is given in Pa·s units,measured in chloroform at 25° C. and at concentration of 0.1% wt/v.

By “satisfactorily controlled” release profile is meant that the implantwill exhibit an initial release profile that is not too steep (fast),which would otherwise lead to plasma levels that are too high withconcomitant toxic side effects, and an initial release profile that isnot too flat (slow), which would lead to plasma levels that are belowtherapeutic concentrations. An implant exhibiting a satisfactorilycontrolled initial release profile will release 0.5 to 20% wt., 1 to 12%wt. or 2 to 8% wt of its charge of risperidone within 24 hours afterbeing placed in an aqueous environment (liquid or subject). It willrelease no more than 20% wt., no more than 15% wt, no more than 12% wt,no more than 10% wt, no more than 8% wt or no more than 6% wt of itscharge of risperidone within 24 hours after being placed in an aqueousenvironment. It will release at least 0.1% wt, at least 0.5% wt., atleast 1% wt, at least 2% wt., at least 3% wt or at least 4% wt of itscharge of risperidone within 24 hours after being placed in an aqueousenvironment. The invention includes all combinations of the embodimentsherein.

The compositions of the invention comprise at least a polymer or polymermatrix, a solvent and a drug. The polymer is preferably a biocompatibleand biodegradable polymer or polymer matrix. In order not to causesevere damage to the body following administration, the preferredpolymers are biocompatible, non-toxic for the human body, notcarcinogenic, and do not induce significant tissue inflammation. Thepolymers are preferably biodegradable in order to allow naturaldegradation by body processes, so that they are readily disposable anddo not accumulate in the body. In selecting the appropriate grade ofPLGA copolymer, the time required for degradation of PLGA is related tothe monomer ratio used in production: the higher the content ofglycolide units, the lower the time required for degradation. Inaddition, polymers that are end-capped with esters (as opposed to thefree carboxylic acid) demonstrate longer degradation half-lives. Thepreferred polymers are selected from end-capped terminal carboxylicpoly-lactide and poly-glycolic acid copolymers (PLGA) mixed in a ratiofrom 50:50 to 75:25 (ratio of lactic acid monomer to glycolic acidmonomer), with an intrinsic or inherent viscosity preferably in therange of 0.16-0.60 dl/g, in the range of 0.2-0.5 dl/g, and morepreferably between 0.25-0.48 dl/g, as measured in chloroform at 25° C.and at a concentration of 0.1% wt/v with a Ubbelohde size 0c glasscapillary viscometer (RESOMER® grades) or as measured in chloroform at30° C. and at a concentration of 0.5% wt/v with a size 25 Cannon-Fenskeglass capillary viscometer (LAKESHORE MATERIALS™ grades). In someembodiments, the PLGA copolymer has a lactic acid to glycolic acidmonomer ratio ranging from 48:52 to 52:48 or 48:52 to 77:23.

The concentration of the polymeric component in the compositions of theinvention is preferably in the range of 25-50%, (expressed as thepercentage of polymer weight based on total polymeric solutioncomponent) and more preferably between 30-40%. Suitable grades of PLGAcopolymers as described herein (according to molecular weight, intrinsicviscosity and/or molar ratio of lactic acid monomer to glycolic acidmonomer) are end-capped (such as with an ester group, e.g. lauryl ester,methyl ester) are available from EVONIK® (Essen, Germany), BoehringerIngelheim (Ingelheim am Rhein, Germany), ALKERMES (Dublin, Ireland) orSIGMA ALDRICH (ST. Louis, Mo.) and are marketed under the tradenamesRESOMER®, LAKESHORE BIOMATERIALS™, or MEDISORB®. As the composition ofsome grades of end-capped PLGA is proprietary, the identity of the esterend-cap is not publicly available. Nonetheless, the performanceproperties of the grades of PLGA copolymer described herein are knownand are used to characterize the material. In some embodiments, the PLGAcopolymer has an intrinsic viscosity, before irradiation, that isunsuitable for use in the injectable composition but, after irradiation,has an intrinsic viscosity that is suitable. Accordingly, a commercialmaterial having an initially high intrinsic viscosity can still be usedin the injectable composition provided it is irradiated so as to reduceits intrinsic viscosity to a value specified herein.

As used herein, the term intrinsic or inherent viscosity (η_(inh)) ofthe polymer is defined as the ratio of the natural logarithm of therelative viscosity, η_(r), to the mass concentration of the polymer, c,i.e.:

η_(inh)=(ln η_(r))/c

and the relative viscosity (η_(r)) is the ratio of the viscosity of thesolution η to the viscosity of the solvent η_(s), i.e.:

η_(r)=η/η_(s)

If not otherwise specified, the intrinsic viscosity values throughoutthe present specification are to be understood as measured at 25° C. inchloroform at a concentration of 0.1%. The value of intrinsic viscosityis considered in the present specification, as commonly accepted in theart, as an indirect indicator of the polymer molecular weight. In thisway, a reduction in the intrinsic viscosity of a polymer, measured at agiven concentration in a certain solvent, with same monomer compositionand terminal end groups, is an indication of a reduction in the polymermolecular weight (IUPAC. Basic definitions of terms relating topolymers; Pure Appl. Chem. (1974) 40, 477-491).

Suitable solvents are non-toxic, biocompatible and appropriate forparenteral injection. Solvents susceptible of causing toxicity shouldnot be used for the injection of any material into any living body.Preferably, solvents are biocompatible in order not to cause severetissue irritation or necrosis at the injection site. Therefore, thesolvent is preferably classified as class II or Ill, and more preferablyclass III, according to ICH Guidelines. For the formation of the in-situimplant, the solvent should preferably diffuse quickly from thepolymeric solution towards surrounding tissues when is exposed tophysiological fluids. Consequently, the solvent is preferably watermiscible and more preferably with a dipole moment about 3.9-4.3 D at 25°C. The preferred solvents are DMSO (dimethylsulfoxide), and PEG(poly(ethylene glycol, such as PEG having an average molecular weight inthe range of about 200, about 300 or about 400). Grades of PEG that areliquid at ambient temperature (20-30° C.) may be used. The mostpreferred solvent is DMSO. The invention also includes an injectablecomposition having a combination of two or more of these solvents.

In some embodiments, the drug is completely dissolved, partiallydissolved or completely undissolved in the solvent used to form thepolymeric solution to form the injectable composition. The drug ispreferably at least partly suspended, i.e. only partially dissolved, inthe solvent or polymeric solution. In some embodiments, ≤5%, ≤10%, ≤20%,≤30%, ≤40%, ≤50%, ≤60%, ≤70%, ≤80%, ≤90%, ≤95% or ≤99% wt of the drug isdissolved in the solvent or polymeric solution to form the injectablecomposition. In some embodiments, ≥1%, ≥5%, ≥10%, ≥20%, ≥30%, ≥40%,≥50%, ≥60%, ≥70% or up to about 80% wt. of the drug is dissolved in thesolvent or polymeric solution to form the injectable composition.

The water solubility of the drug in the solvent is preferably less thanabout 90 mg/ml, more preferably less than about 65 mg/ml, and mostpreferably below about 10 mg/ml. The advantage of this low solubility isthat the initial burst of the drug when the solvent diffuses into theexternal aqueous medium, following placement therein, is greatlyreduced.

In some embodiments, the concentration of drug in the injectablecomposition is generally in the range of about 4 and 16 wt %, expressedas the percentage of the drug with respect to the total compositionweight. More preferably, the drug content is between 7 and 15% wt, andmost preferably about 13% wt with respect to the total compositionweight.

One of the factors contributing to controlling the initial release ofdrug from the implant, after placement in an aqueous environment, is theviscosity of the polymeric solution of the injectable composition. Theterm “polymeric solution” is defined as the combination of the polymermatrix and the solvent in which it is dissolved. In some embodiments,the polymeric solution has a viscosity in the range of about 0.2-7.0Pa·s, about 0.5-7.0 Pa·s, more preferably about 0.5-3.0 Pa·s, and mostpreferably about 0.7-3.0 Pa·s, or about 0.7-2.0 Pa·s.

Another factor contributing to controlling the initial release of drugfrom the implant is the risperidone/polymer mass ratio of the injectablecomposition. In some embodiments, this mass ratio, expressed as thepercentage of the drug weight with respect to total weight of the drugplus polymer, is in the range of about 15-40% weight, more preferablyabout 25-35% wt, and most preferably about 33% wt.

Yet another factor contributing to controlling the initial release ofdrug from the implant is the drug's particle size. Large particlesprovide a smaller surface area per weight thereby reducing the initialrelease (burst) but the release may be then delayed until the beginningof the degradation of the polymeric matrix. On the other hand, smallparticles evoke higher burst levels due to increased surface area andeasier drug diffusion from small particles during implant hardening,followed by continuous drug release levels due to the combination of theprocesses of drug diffusion and implant erosion. Consequently, in apreferred embodiment of the invention a wide particle size distribution,combining large and small particle sizes in different ratios, is used inorder to reduce the initial burst and still maintain a suitable constantdrug release by diffusion of smaller particles during the first phase ofrelease and gradual release of drug from the bigger particles while thepolymer degrades, i.e. during the period of time (days to weeks)following the initial burst phase. In some embodiments, the particlesize distribution of the drug is as follows: not more than 10% of thetotal volume of drug particles are less than 10 microns in size(equivalent diameter in volume as a function of applying Fraunhofertheory to irregularly shape particles; as measured by laser lightscattering, such as with a Malvern Mastersizer 2000) and not more than10% of the total volume of drug particles are greater than 225 micronsin size. In addition, the drug particles possess a d0.5 value preferablyin the range of about 60-130 microns. Accordingly, in some embodiments,the risperidone comprises a broad particle size distribution, which canbe monomodal, bimodal or trimodal.

In addition to the above factors, the following ratios between thecomponents of the compositions according to the invention can alsocontribute toward controlling the initial release of drug from theimplant: a) mass ratio between the amounts of polymeric solution(polymer+solvent) and risperidone in the injectable composition; b) massratio between the amounts of solvent and risperidone (mg solvent/mgrisperidone) in the injectable composition; c) the presence or absenceof an alkaline agent in the injectable composition.

In some embodiments, the mass ratio of the amount of polymeric solution(polymer+solvent) to the amount of risperidone in the injectablecomposition ranges from about 15:1 to 5:1, more preferably from about12:1 to 5:1, about 12:1 to about 2:1, about 7:1 to about 2.5:1 or about6.7:1 to 3:1, and most preferably from about 7:1 to 6.5:1. In the mostpreferred embodiments, this mass ratio is about 6.66:1, or as describedin the examples below (see Example 12).

In some embodiments, the mass ratio of the amount of solvent and theamount of risperidone (mg solvent/mg risperidone) in the injectablecomposition ranges from about 12:1 to 4:1, more preferably about 10:1 to4:1 and most preferably about 5:1 to 4:1. In the most preferredembodiments, this mass ratio is about 4.66:1 (see Example 13 below).This ratio defines (is related to) the rate of hardening of the implantby solvent diffusion and consequently the precipitation of the polymerafter the injectable composition is placed in a aqueous environment.Hence, this parameter is also related to the proportion of drugdissolved/dispersed in the polymeric solution and therefore it controlswhether further drug is diffused from the implant or not.

Optionally, an alkaline agent with low water solubility such as lowerthan 0.02 mg/ml can be included within the polymer matrix. The alkalineagent can be present in a molar ratio of from about 3/1 to 2/5 or >about2/5 (drug/alkaline agent), meaning that the alkaline agent is present inmolar excess over the drug. Preferred alkaline agents are alkaline oralkaline-earth hydroxides, such as magnesium hydroxide or aluminumhydroxide. Due to the limited water solubility of the alkaline agent,the d 0.5 of the particle size distribution, e.g. of the magnesiumhydroxide, is preferably below 10 microns.

The invention also provides an injectable composition that forms asingle solid body implant in a subject to which it is administered, thecomposition comprising:

-   -   a. a polymeric solution comprising a biodegradable        poly(L-lactide-co-glycolide) polymer having a monomer ratio of        lactic acid to glycolic acid in the range of about 50:50 to        75:25, and a solvent having a dipole moment in the range of        3.9-4.3 D; and    -   b. drug-containing particles of risperidone, a metabolite of        risperidone, a prodrug of risperidone or a combination thereof        dispersed in the polymeric solution, the particles having a size        distribution as follows: not more than 10% of the total volume        of drug particles is less than 10 microns in size, not more than        10% of the total volume of drug particles is greater than 225        microns in size, and the d0.5 of the size distribution being in        the range of about 60-130 microns.

The invention also provides an injectable composition that forms asingle solid body implant in a subject to which it is administered, thecomposition comprising:

-   -   a. a polymeric solution comprising a biodegradable        poly(L-lactide-co-glycolide) polymer having a monomer ratio of        lactic acid to glycolic acid in the range of about 50:50 to        75:25, and a solvent having a dipole moment in the range of        3.9-4.3 D; and    -   b. drug-containing particles of risperidone, a metabolite of        risperidone, a prodrug of risperidone or a combination thereof        dispersed in the polymeric solution, the particles having a size        distribution as follows: not more than 10% of the total volume        of drug particles is less than 10 microns in size, not more than        10% of the total volume of drug particles is greater than 225        microns in size, and the d0.5 of the size distribution being in        the range of about 60-130 microns; wherein    -   c. the intrinsic or inherent viscosity of the polymer is in the        range of about 0.16 to about 0.60 dl/g when measured in        chloroform at 25° C. and a 0.1% concentration.

The invention also provides an injectable composition that forms asingle solid body implant in a subject to which it is administered, thecomposition comprising:

-   -   a. a polymeric solution comprising a biodegradable        poly(L-lactide-co-glycolide) polymer having a monomer ratio of        lactic acid to glycolic acid in the range of about 50:50 to        75:25, and a solvent having a dipole moment in the range of        3.9-4.3 D; and    -   b. drug-containing particles of risperidone, a metabolite of        risperidone, a prodrug of risperidone or a combination thereof        dispersed in the polymeric solution, the particles having a size        distribution as follows: not more than 10% of the total volume        of drug particles is less than 10 microns in size, not more than        10% of the total volume of drug particles is greater than 225        microns in size, and the d0.5 of the size distribution being in        the range of about 60-130 microns; wherein    -   c. the viscosity of the polymeric solution is in the range of        about 0.5-7.0 Pa·s.

The invention also provides an injectable composition that forms asingle solid body implant in a subject to which it is administered, thecomposition comprising:

-   -   a. a polymeric solution comprising a biodegradable        poly(L-lactide-co-glycolide) polymer having a monomer ratio of        lactic acid to glycolic acid in the range of about 50:50 to        75:25, and a solvent having a dipole moment in the range of        3.9-4.3 D; and    -   b. drug-containing particles of risperidone, a metabolite of        risperidone, a prodrug of risperidone or a combination thereof        dispersed in the polymeric solution, the particles having a size        distribution as follows: not more than 10% of the total volume        of drug particles is less than 10 microns in size, not more than        10% of the total volume of drug particles is greater than 225        microns in size, and the d0.5 of the size distribution being in        the range of about 60-130 microns; wherein    -   c. the concentration of drug-containing particles in the        injectable composition is in the range of about 4 and 16 wt %,        expressed as the percentage of the drug-containing particles        with respect to the total composition weight, or the mass ratio        of the amount of polymeric solution (polymer+solvent) and to the        amount of drug-containing particles in the injectable        composition ranges from about 15:1 to about 5:1.

The invention also provides an injectable composition that forms asingle solid body implant in a subject to which it is administered, thecomposition comprising:

-   -   a. a polymeric solution comprising a biodegradable        poly(L-lactide-co-glycolide) polymer having a monomer ratio of        lactic acid to glycolic acid in the range of about 50:50 to        75:25, and a solvent having a dipole moment in the range of        3.9-4.3 D; and    -   b. drug-containing particles of risperidone, a metabolite of        risperidone, a prodrug of risperidone or a combination thereof        dispersed in the polymeric solution, the particles having a size        distribution as follows: not more than 10% of the total volume        of drug particles is less than 10 microns in size, not more than        10% of the total volume of drug particles is greater than 225        microns in size, and the d0.5 of the size distribution being in        the range of about 60-130 microns; wherein    -   c. the concentration of polymer in the injectable composition is        in the range of about 25-50% expressed as the percentage of        polymer weight based on total polymeric solution component.

The invention also provides an injectable composition that forms asingle solid body implant in a subject to which it is administered, thecomposition comprising:

-   -   a. a polymeric solution comprising a biodegradable        poly(L-lactide-co-glycolide) polymer having a monomer ratio of        lactic acid to glycolic acid in the range of about 50:50 to        75:25, and a solvent having a dipole moment in the range of        3.9-4.3 D; and    -   b. drug-containing particles of risperidone, a metabolite of        risperidone, a prodrug of risperidone or a combination thereof        dispersed in the polymeric solution, the particles having a size        distribution as follows: not more than 10% of the total volume        of drug particles is less than 10 microns in size, not more than        10% of the total volume of drug particles is greater than 225        microns in size, and the d0.5 of the size distribution being in        the range of about 60-130 microns; wherein    -   c. the composition has a solvent/drug mass ratio ranging from        about 10:1 to about 4:1.

Another aspect of the invention is directed to a kit comprising: a firstcontainer containing a polymer in solid form, risperidone and optionallyMg(OH)₂ in predetermined amounts; and a second container containing awater-miscible solvent. When required, the contents of both containersare combined, for example through a connector or by using male-femalesyringes, and mixed each other so that the compositions according to theinvention are reconstituted, for example by moving forwards andbackwards the plungers of the syringes. The polymer is preferably PLGA,which is preferably provided in freeze-dried (lyophilized) form. Eachcontainer is independently selected at each occurrence from a syringe,vial, device and cartridge. Each container is independently at eachoccurrence disposable or not disposable. Illustrative preferredembodiments of the containers are depicted in FIG. 35 (syringesconnected through a connector device) and in FIG. 36 (syringes connectedthrough a direct thread).

The invention also provides an injectable composition that forms asingle solid body implant in a subject to which it is administered, thecomposition comprising:

-   -   a. a polymeric solution comprising a biodegradable        poly(L-lactide-co-glycolide) polymer having a monomer ratio of        lactic acid to glycolic acid in the range of about 50:50 to        75:25, and a solvent having a dipole moment in the range of        3.9-4.3 D, wherein the solvent is present in an amount        sufficient to dissolve at least 95% of the polymer;    -   b. drug-containing particles of risperidone, a metabolite of        risperidone, a prodrug of risperidone or a combination thereof        at least partially dispersed in the polymeric solution, the        particles having a size distribution as follows: not more than        10% of the total volume of drug particles is less than 10        microns in size, not more than 10% of the total volume of drug        particles is greater than 225 microns in size, and the d0.5 of        the size distribution is in the range of about 60-130 microns;        and    -   c. Mg(OH)₂ present in molar excess over the moles of drug.

In a preferred embodiment, the injectable depot compositions of theinvention further comprise Mg(OH)₂ at a molar ratio in the range ofabout 2/3 to 2/5, expressed as the molar ratio of drug to Mg(OH)₂.

In some embodiments, the injectable depot composition is sterile as afinished product. The biocompatible polymer can be sterilized prior toits aseptic filling process, preferably by an aseptic filling process bybeta-irradiation in the range 5-25 KGy or 10-25 KGy or it can besterilized after being dissolved in a solvent to form a polymericsolution followed by filtration of the polymeric solution through afilter with a 0.22 μm pore size or less. In some embodiments, thepolymer is irradiated alone or prior to mixing with solvent or drug. Insome embodiments, the polymer is irradiated in solid form. In someembodiments, the polymeric solution is irradiated prior to mixing withdrug.

The polymer can be sterilized by 3-irradiation. Example 15 describes anexemplary process for sterilization of the composition. The polymer andrisperidone were mixed and subjected to 3-irradiation in the range 10-25KGy. Exposure to radiation caused the polymer to degrade therebyresulting in a polymer with reduced molecular weight and a correspondingpolymer solution with reduced viscosity. In some embodiments, theinvention provides a process for preparing an injectable composition asdescribed herein, the process comprising: a) subjecting a PLGA polymerto a sufficient amount of 3-irradiation to degrade at least a portion ofthe polymer thereby reducing its molecular weight; and b) dissolving thepolymer in a solvent to form a polymeric solution having a desiredviscosity. In some embodiments, a mixture of drug and PLGA polymer areexposed to beta-irradiation prior to addition of the solvent, whichwould result in formation of a sterilized injectable composition of theinvention.

Embodiments of the invention include those wherein: a) the molecularweight of the polymer is greater before irradiation than it is afterirradiation; b) the molecular weight of the polymer is greater thanabout 10 KDa or greater than about 15 KDa before irradiation; c) themolecular weight of the polymer is in the range of 15-60 KDa, 25-52 KDaor 28-43 KDa after irradiation; d) the viscosity of a polymeric solutioncontaining polymer that has not been irradiated is greater than about0.5 Pa·s; e) the viscosity of a polymeric solution containing polymerthat has been irradiated is in the range of 0.5-7.0 Pa·s, 0.5-3.0 Pa·sor 0.7 to 2.0 Pa·s.; and/or f) the sufficient amount of radiation is atleast 10, at least 15, at least 20 or at least 25 KGy.

In another preferred embodiment, in the injectable depot composition atleast the drug and/or the biocompatible polymer of the composition havebeen submitted to terminal sterilization processes, preferably byirradiation in the range of 5-25 KGy.

The injectable composition is used to treat a disorder, disease orcondition that is therapeutically responsive to risperidone or ametabolite thereof. The invention comprises administering to a subjectin need thereof an amount of injectable composition sufficient toprovide therapeutic plasma levels of risperidone in the subject duringthe period of at least 1 to 14, at least 2 to 14 or at least 3 to 14days after administration (the dosing period). The dosing period canexceed two weeks.

In humans, the average plasma concentration of risperidone can rangefrom about 3-200, about 5-80, or about 10-60 ng/ml when an amount ofinjectable composition equivalent to a dose of about 25-150, about37.5-125, or about 50-100 mg of risperidone is administered. The averageCmin during the dosing period is in the range of about 1-80, 5-50, orabout 5-40 ng/ml when an amount of injectable composition equivalent toa dose of about 25-150, about 37.5-125, or about 50-100 mg,respectively, of risperidone is administered. The average Cmax duringthe dosing period is in the range of about 8-300, 10-150, or 10-120ng/ml when an amount of injectable composition equivalent to a dose of25-150, 37.5-125, or 50-100 mg, respectively, of risperidone isadministered. Some individual subjects may, on an equivalent dose basis,exhibit plasma concentrations outside the ranges specified herein forreasons such as poor health, advanced age, compromised metabolism, renalfailure, disease, etc. Even so, a majority of subjects in a patientpopulation to which the injectable implant is administered will exhibitplasma concentrations with those specified herein.

The implant of the invention can provide substantially improved plasmalevels of risperidone during the initial one to three days afteradministration when compared to the RISPERIDAL CONSTA injectableformulation when administered on an equivalent dose basis. The implantof the invention can provide substantially the same average plasmalevels of risperidone during a full dosing period after administrationwhen compared to the RISPERIDAL CONSTA injectable formulation whenadministered on an equivalent dose basis.

As used herein, whenever the plasma concentration of risperidone ismentioned, such plasma concentration includes within it the sum total ofthe plasma concentrations of risperidone and its metabolite(s), such as9-OH-risperidone (paliperidone).

The plasma concentration profile during the dosing period can exhibitone, two, or more maxima and one, two or more minima. An initial maximumcan be caused by dissolution of risperidone during the initial day(s) ofthe dosing period followed by a slowing of the release thereof andanother maximum can be caused by increased rate of release during theremaining days of the dosing period. Embodiments of the inventioninclude those wherein: a) the plasma profile exhibits a maximum duringthe initial one to three days or one to two days of the dosing period;b) the plasma profile exhibits a maximum during the latter 11 to 13 daysor 12 to 14 days of the dosing period; c) the plasma profile exhibits amaximum during the initial days of the dosing period and a maximumduring the remaining days of the dosing period; or d) the plasma profileis substantially level (within ±20%, ±15%, ≥10% or ±5% of the average ormean) during the dosing period.

As used herein, the term “dosing period” refers to the period of days orweeks as measured from the initial day after administration to at least14 days after administration. During the dosing period, the implant willprovide therapeutic plasma levels of risperidone for at least 11 days,at least 12 days, at least 13 days, at least 14 days, at least 21 days,at least 28 days, at least 31 days or at least 36 days. A dosing periodcan end after expiration of a predetermined number of days or after theplasma level of risperidone drops below therapeutic levels. A dosingperiod of at least 4 weeks is preferred.

As used herein, a “treatment period” refers to the weeks, months oryears during which implants of the invention are administered to asubject. A treatment period generally comprises plural dosing periods.Dosing periods can occur sequentially or in an overlapping manner duringa treatment period. For example, a first dose of injectable compositionis administered and a second dose of injectable composition can beadministered within one to three weeks following administration of thefirst dose, such that each dose will have its own corresponding dosingperiod, and the dosing periods would overlap. Dosing periods willtypically be sequentially or overlap by no more than one or two days.

The injectable composition can be administered to a subject in one ormore injection sites on the same day and still be considered as beingpart of the same dosing period. For example, part of a dose can beadministered to a first injection site and another part of the same dosecan be administered to another injection site. A single-body implantwill form at each injection site. Such a mode of administration within asame day is considered to be administration of a single dose with asingle dosing period.

Alternatively, administration can be modified such that there is onepoint of needle entry into the subject but more than one injection sitebelow the skin, which can be achieved by making a first penetration intothe skin and muscle and administering a portion of a dose, thenpartially withdrawing and redirecting the needle into another section ofmuscle, while maintaining the tip of the needle beneath the skin, andthen injecting another portion of the dose into this other section ofmuscle. Such a mode of administration is still considered to beadministration of a single dose within a single dosing period.

The plasma concentration profile during the dosing period can exhibitone, two, or more maxima and one, two or more minima. An initial maximumcan be caused by dissolution of risperidone during the initial day(s) ofthe dosing period followed by a slowing of the release thereof andanother maximum can be caused by increased rate of release during theremaining days of the dosing period. Embodiments of the inventioninclude those wherein: a) the plasma profile exhibits a maximum duringthe initial one to six days or one to three days of the dosing period;b) the plasma profile exhibits a maximum during the latter 14 to 24 daysof a 4-week dosing period; c) the plasma profile exhibits a maximumduring the initial days of the dosing period and a maximum during theremaining days of the dosing period; or d) the plasma profile issubstantially level (within 20%, ±15%, ±10% or ±5% of the average ormean) during the dosing period.

The implant of the invention can provide substantially improved plasmalevels of drug during the initial one to three days after administrationwhen compared to another injectable formulation (not according to theinvention) containing the same drug when administered on an equivalentdose basis.

As used herein the term, “initial burst” or “initial release” refers tothe addition of the plasma levels of risperidone plus those of9-OH-risperidone, which addition is also called “the active moiety”throughout the present specification, from the moment ofinjection/administration of the injectable composition to a subject inneed thereof until completion of the third day after the administration.For example, the drug can be risperidone and its metabolite can bepaliperidone. In some embodiments, the initial period of release iswithin three days, within two days, within one day or within twelvehours after administration.

Acceptable plasma levels of active moiety during the initial burst phaseare below 100 ng/ml in Beagle dogs and New Zealand White Rabbits whenthe dose of injectable composition administered is 2.5 mg/kg risperidonein dogs and 5 mg/kg risperidone in rabbits.

The following examples illustrate the invention and should not beconsidered as defining the full scope thereof.

Comparative Example 1: Implantable Composition Including aWater-Insoluble Solvent (Example not According to the Invention)

In the present example, the composition of the implantable formulationwas as follows:

Ingredient Amount (mg) Resomer ®RG752S (polymer) 100 Risperidone 25Benzyl benzoate (solvent) 233.3 RG752S, 75:25 lactic/glycolic acidpolymer (Boehringer Ingelheim)

The risperidone implantable formulation was prepared by completelydissolving the polymer in the solvent and subsequently suspending thedrug in said polymeric solution to form an injectable drug suspension.

In Vitro Release Profile:

The risperidone release from the formulation of this example wasevaluated according to the following procedure. The amount offormulation corresponding to 25 mg of risperidone was injected fromprefilled syringes having 21G needles into flasks having a pre-warmedrelease medium. The release medium was 250 ml phosphate buffer, pH=7.4.The flasks were then placed into an oven at 37° C. and kept underhorizontal shaking at 50 rpm. At previously scheduled time points (2 h,1 d, 3 d, 6 d, 8 d, 10 d, 13 d, 17 d, 21 d, 23 d, 28 d, 31 d, 35 d, 42d), 5 ml of release medium was collected and replaced with fresh bufferand the amount of risperidone present in the sample was determined by UVspectrophotometry. The profile of risperidone released from the implantsof this example is shown in FIG. 1. The results are expressed as %Risperidone released from implants as a function of time.

As depicted in FIG. 1, the release of risperidone during the first 24hours is close to 20% of the injected amount and close to 50% in thefirst 48 hours. This finding is not in accordance with previousteachings such as U.S. Pat. No. 6,673,767, since this low water-misciblesolvent is clearly unable to control the initial diffusion ofrisperidone from the polymer matrix.

In Vivo Plasma Levels after Intramuscular Administration to New ZealandRabbit:

The risperidone composition of this example was injected intramuscularlyto New Zealand White rabbits weighing an average of 3 kg. The amountinjected corresponded to a dose of 15 mg risperidone, and thecomposition was injected intramuscularly into the left hind leg using asyringe equipped with a 20G needle. Total number of rabbits was 3. Afterinjection, plasma levels were obtained at 0, 4 h, 1 d, 2 d, 3 d, 5 d, 7d, 10 d, 14 d, 17 d, 21 d, 24 d and 28 d.

The kinetics of the plasma levels corresponding to the risperidoneactive moiety was evaluated by measuring both risperidone and its activemetabolite 9-OH-risperidone in the plasma samples. The profile of theplasma levels of the risperidone active moiety is shown in FIG. 2. Theresults are expressed as the addition of risperidone plus9-OH-risperidone concentrations (ng/ml) as the function of time, sincethe therapeutic activity of 9-OH-risperidone is substantially equivalentto that of risperidone. As depicted in FIG. 2, the injection of anamount of composition equivalent to 15 mg risperidone to New ZealandWhite rabbits resulted in very high initial plasma levels followed by arapid decrease, with no significant plasma levels from day 3 onwards.All 3 animals exhibited severe adverse effects related to the very highplasma levels of risperidone active moiety 15 min after the injection,which demonstrates the rather poor control on the initial drug releaseachieved with this composition.

Example 1: Study of Different Water-Soluble Solvents with DifferentDipole Moment

In the present example, the composition of the implantable formulationwas as follows:

Composition 1 Composition 2 Solvent dipole Ingredient Amount (mg) moment(D) Resomer ®RG503 100 100 (polymer) Risperidone 25 25 Dimethylsulfoxide 233.3 — 3.96 (solvent) 1,4-dioxane (solvent) — 233.3 0.45RG503, 50:50 lactic/glycolic acid polymer (Boehringer Ingelheim)

The risperidone-implantable formulation was prepared by completelydissolving the polymer in either of the cited water-miscible solventshaving different dipole moment (DMSO or 1,4-dioxane) and subsequentlysuspending the drug in said polymeric solution.

In Vitro Release Profile:

The risperidone release from the formulations of this example wasevaluated according to the following procedure: the amount offormulation corresponding to 25 mg of risperidone was injected fromprefilled syringes equipped with 21G needles into flasks followed bycareful addition of a pre-warmed release medium. The release medium was250 ml phosphate buffer, pH=7.4. The flasks were then placed into anoven at 37° C. and kept under horizontal shaking at 50 rpm. Atpreviously scheduled time points (2 h, 1 d, 3 d, 6 d, 8 d, 10 d, 13 d,17 d, 21 d, 23 d, 28 d, 31 d, 35 d, 42 d), 5 ml of release medium wascollected and replaced with fresh buffer, and the amount of risperidoneamount present in the sample was determined by UV spectrophotometry.

The profile of the risperidone released from the formulations is shownin FIG. 3. The results are expressed as % Risperidone released from theimplants as a function of time. As depicted in FIG. 3, and in comparisonwith FIG. 1 (corresponding to Comparative Example 1), the use of watermiscible solvents versus water-immiscible solvents in the implantablecompositions of the invention allows for a more precise control of theinitial release of risperidone from the polymer matrix. The presentexample also shows the influence of the dipole moment of the solvent inthe release of risperidone from the implantable compositions of theinvention: The use of solvents with lower dipole moment (dioxane) causesa higher risperidone initial diffusion than solvents having higherdipole moment solvents (DMSO) about 3.9-4.3 D, which solvents notablyreduce the drug diffusion during 2 weeks.

Example 2: Study of Solvents with a High Solubility for Risperidone

In the present example, the composition of the implantable formulationwas as follows:

Ingredient Amount (mg) Resomer ®RG752S (polymer) 100 Risperidone 25Benzyl alcohol (solvent) 233.3 RG752S, 75:25 lactic/glycolic acidpolymer (Boehringer Ingelheim)

The risperidone-implantable formulation of this example was prepared bycompletely dissolving the polymer in the water-miscible solvent having ahigh solubility for risperidone (benzyl alcohol) and subsequentlysuspending the drug in said polymeric solution.

In Vitro Release Profile:

The release of risperidone from the formulation was evaluated accordingto the following procedure: the amount of formulation corresponding to25 mg of risperidone was injected from prefilled syringes equipped witha 21G needle into flasks having a pre-warmed release medium. The releasemedium was 250 ml phosphate buffer, pH=7.4. The flasks were then placedinto an oven at 37° C. and kept under horizontal shaking at 50 rpm. Atpreviously scheduled time points (2 h, 1 d, 3 d, 6 d, 8 d, 10 d, 13 d,17 d, 21 d, 23 d, 28 d, 31 d, 35 d, 42 d), 5 ml of release medium wascollected and replaced with fresh buffer, and the amount of risperidonepresent in the sample was determined by UV spectrophotometry.

The profile of risperidone released from the formulation is shown inFIG. 4. The results are expressed as % Risperidone released from theimplants as a function of time. As depicted in FIG. 4, the use ofsolvents having a high solubility for risperidone as in the presentexample results in a high initial risperidone diffusion and a drugrelease from the polymer matrix close to 30% in the first 3 days andalong the first week.

In Vivo Plasma Levels after Intramuscular Administration to New ZealandRabbit

The risperidone composition of this example was injected intramuscularlyinto New Zealand White rabbits weighing an average of 3 kg. The amountinjected corresponded to a dose of 15 mg risperidone and the compositionwas placed intramuscularly in the left hind leg using a syringe with a20G needle. Total number of rabbits was 3. After injection, plasmalevels were obtained at 0, 4 h, 1 d, 2 d, 3 d, 5 d, 7 d, 10 d, 14 d, 17d, 21 d, 24 d and 28 d.

The kinetics of the plasma levels corresponding to the risperidoneactive moiety was evaluated by measuring both risperidone and its activemetabolite 9-OH-risperidone in the plasma samples. The profile of therisperidone active moiety plasma levels is depicted in FIG. 5. Theresults are expressed as the addition of the risperidone plus9-OH-risperidone concentrations (ng/ml) as the function of time, sincethe therapeutic activity of 9-OH-risperidone is substantially equivalentto that of risperidone. As depicted in the figure, the injection of thetested composition in an amount equivalent to 15 mg risperidone to NewZealand White rabbits resulted in very high initial plasma levelsfollowed by a rapid decrease, with no significant plasma levels from day5 onwards. All 3 animals exhibited adverse effects related to the veryhigh plasma levels of risperidone active moiety 15 min after theinjection, which demonstrates the very poor control on the initial drugrelease achieved with this composition, which comprises a solvent havinga high solubility for risperidone.

Example 3: Study of Solvents with Different Solubility for Risperidone

In the present case, the risperidone implantable formulation wasprepared by completely dissolving the polymer Resomer® RG503 (RG503,50:50 lactic/glycolic acid, Boehringer Ingelheim) in different solvents(NMP, PEG and DMSO) in which risperidone exhibits intermediate to lowsolubility (in all cases below 65 mg/ml) and subsequently suspending therisperidone in the respective solvent.

Composition 1 Composition 2 Composition 3 (DMSO) (NMP) (PEG300)Ingredient Amount (mg) Risperidone 25 25 25 Resomer ®RG503 100 100 66.6(polymer) DMSO 233.3 — — NMP — 233.3 — PEG — — 266.7 Risperidonesolubility: 62.5 mg/mL in NMP; 9.5 mg/mL in DMSO; 8.2 mg/mL in PEG300

In Vitro Release Profile:

The risperidone release from the formulations of this example wasevaluated according to the following procedure: the amount offormulation corresponding to 25 mg of risperidone was injected fromprefilled syringes equipped with a 21G needle into flasks followed bythe careful addition of a pre-warmed release medium. The release mediumwas 250 ml phosphate buffer pH=7.4. The flasks were then placed into anoven at 37° C. and kept under horizontal shaking at 50 rpm. Atpreviously scheduled time points (2 h, 1 d, 3 d, 6 d, 8 d, 10 d, 13 d,17 d, 21 d, 23 d, 28 d, 31 d, 35 d, 42 d), 5 ml of release medium wascollected and replaced with fresh buffer, and the amount of risperidonepresent in the sample was determined by UV spectrophotometry.

The profile of risperidone released from the formulations is shown inFIG. 6. The results are expressed as % Risperidone released from theformulations as a function of time. As depicted in FIG. 6, the use of asolvent having a lower risperidone solubility (in comparison to highsolubility as in FIG. 4 from Example 2) offers initial controlledrisperidone diffusion from the polymer matrix and a controlled releaseup to at least 28 days. Hence, the use of solvents having a lowsolubility for risperidone, such as DMSO, as in the present example,allows a more precise control of the drug released during the solventdiffusion and the polymer precipitation.

Example 4: Study of Different Polymer Concentrations with Respect to theSolvent

In the present example, the compositions of the implantable formulationswere as follows:

Composition 1 Composition 2 Composition 3 Composition 4 IngredientAmount (mg) Risperidone 25 25 25 25 Resomer ® RG503 33.3 66.5 100 190(polymer) Dimethyl sulfoxide 300 266.8 233.3 285 (solvent) Polymer (%,w/w respect to polymer + solvent) concentration 10 20 30 40 RG503, 50:50lactic/glycolic acid (Boehringer Ingelheim)

The above values are otherwise expressed as follows:

Composition 1 Composition 2 Composition 3 Composition 4 IngredientAmount (%) Resomer ® RG503 10 20 30 40 (polymer) Dimethyl sulfoxide 9080 70 60 (solvent)

The risperidone-implantable formulations were prepared by completelydissolving the polymer in the solvent in different proportions andsubsequently suspending the drug in said polymeric solution.

In Vitro Release Profile:

The risperidone release from the formulations of this example wasevaluated according to the following procedure: the amount offormulation corresponding to 25 mg of risperidone was injected fromprefilled syringes by using a 21 G needle into flasks followed by thecareful addition of a pre-warmed release medium. The release medium was250 ml phosphate buffer at pH=7.4. The flasks were then placed into anoven at 37° C. and kept under horizontal shaking at 50 rpm. Atpreviously scheduled time points (2 h, 1 d, 3 d, 6 d, 8 d, 10 d, 13 d,17 d, 21 d, 23 d, 28 d, 31 d, 35 d, 42 d), 5 ml of release medium wascollected and replaced with fresh buffer, and the amount of risperidonepresent in the sample was determined by UV spectrophotometry.

The profile of risperidone released from the formulations of thisexample is shown in FIG. 7. The results are expressed as % Risperidonereleased from the formulations as a function of time. As it can beobserved in FIG. 7, the use of polymer matrix solutions having a lowpolymer concentration (10% w/w), produces an extremely high initialrisperidone release, so that the control of risperidone diffusion isvery difficult. Although an increase in the polymer concentration to 20%(w/w) notably improves the capacity to control the risperidone releasedfrom the polymer matrix, it is still not enough to completely controlthe initial risperidone diffusion release, which is close to 15% duringfirst 24 hours. Polymer concentrations at 30 and 40% (w/w) lead to anefficient initial drug release control, achieving controlled releaseprofiles up to 35-42 days.

Example 5: Study of a Low (10%) Polymer Concentration with Respect ofthe Solvent, where the Solvent has a Very High Solubility forRisperidone

In the present example, the composition of the implantable formulationwas as follows:

Ingredient Amount (mg) Resomer ® RG752S (polymer) 100 Risperidone  25Benzyl alcohol (solvent) 900 RG752S, 75:25 lactic/glycolic acid polymer(Boehringer Ingelheim)

The risperidone-implantable formulation was prepared by completelydissolving the polymer in a solvent having a very high solubility forrisperidone (benzyl alcohol) and subsequently suspending the drug insaid polymeric solution. The concentration of the polymer with respectto the solvent was low (10%).

In Vitro Release Profile:

The risperidone release from the formulation of this example wasevaluated according to the following procedure: the amount offormulation corresponding to 25 mg of risperidone was injected fromprefilled syringes equipped with a 21G needle into flasks having apre-warmed release medium. The release medium was 250 ml phosphatebuffer, pH=7.4. The flasks were then placed into an oven at 37° C. andkept under horizontal shaking at 50 rpm. At previously scheduled timepoints (2 h, 1 d, 3 d, 6 d, 8 d, 10 d, 13 d, 17 d, 21 d, 23 d, 28 d, 31d, 35 d, 42 d), 5 ml of release medium was collected and replaced withfresh buffer, and the amount of risperidone present in the sample wasdetermined by UV spectrophotometry.

The profile of risperidone released from the implants is shown in FIG.8. The results are expressed as % Risperidone released from theformulation as a function of time. As depicted in FIG. 8, and in linewith the results shown in FIG. 7 from Example 4, a concentration of thepolymer of 10% (w/w) in the polymeric solution is not enough to retainthe risperidone in the implantable formulations, therefore providing aninitial release of risperidone that is too high during the first days.

In Vivo Plasma Levels after Intramuscular Administration to New ZealandRabbit

The risperidone composition was injected intramuscularly to New ZealandWhite rabbits weighing an average of 3 kg. The amount injectedcorresponded to a dose of 15 mg risperidone and the composition wasplaced intramuscularly into the left hind leg using a syringe with a 20Gneedle. Total number of rabbits was 3. After injection, plasma levelswere obtained at 0, 4 h, 1 d, 2 d, 3 d, 5 d, 7 d, 10 d, 14 d, 17 d, 21d, 24 d and 28 d.

The kinetics of the plasma levels corresponding to the risperidoneactive moiety was evaluated by measuring both risperidone and its activemetabolite 9-OH-risperidone in the plasma samples. The profile of therisperidone active moiety plasma levels is shown in FIG. 9. The resultsare expressed as the addition of the risperidone plus 9-OH-risperidoneconcentrations (ng/ml) as a function of time, since the therapeuticactivity of 9-OH-risperidone is substantially equivalent to that ofrisperidone. As depicted in the figure, the injection of an amount offormulation equivalent to 15 mg risperidone to New Zealand White rabbitsresulted in very high initial plasma levels of risperidone, followed bya rapid decrease, with no significant plasma levels from day 5 onwards.All 3 animals exhibited adverse effects related to the very high plasmalevels of risperidone active moiety 15 min after the injection, whichshows a very poor control on the initial drug release achieved with thiscomposition comprising low polymer concentration in the polymer matrix.

Example 6: Study of Intermediate (25%) Polymer Concentrations withRespect to Solvent

In the present example, the compositions of the implantable formulationwere as follows:

Ingredient Amount (mg) Resomer ® RG503 (polymer) 41.7 Risperidone 25Polyethylene glycol 300 (solvent) 125 RG503, 50:50 lactic/glycolic acidpolymer (Boehringer Ingelheim)

The risperidone-implantable formulations were prepared by completelydissolving the polymer in the solvent and subsequently suspending thedrug in the polymeric solution. The concentration of the polymer withrespect to the solvent was intermediate (25%).

In Vivo Plasma Levels after Intramuscular Administration to New ZealandRabbit

The risperidone composition was injected intramuscularly into NewZealand White rabbits weighing an average of 3 kg. The amount injectedcorresponded to a dose of 15 mg risperidone and the composition wasplaced intramuscularly in the left hind leg using a syringe with a 20Gneedle. Total number of rabbits was 3. After injection, plasma levelswere obtained at 0, 4 h, 1 d, 2 d, 3 d, 5 d, 7 d, 10 d, 14 d, 17 d, 21d, 24 d, 28 d, 31 d, 35 d, 38 d and 42 d.

The kinetics of the plasma levels corresponding to the risperidoneactive moiety was evaluated by measuring both risperidone and its activemetabolite 9-OH-risperidone in the plasma samples. The profile of therisperidone active moiety plasma levels is shown in FIG. 10. The resultsare expressed as the addition of the risperidone plus 9-OH-risperidoneconcentrations (ng/ml) as a function of time, since the therapeuticactivity of 9-OH-risperidone is substantially equivalent to that ofrisperidone. As depicted in the figure, the injection of an amount offormulation equivalent to 15 mg risperidone to New Zealand White rabbitsresulted in moderate initial plasma levels followed by a decrease untilday 2 and sustained plasma levels at least up to 24 days. The resultsobtained in this example are in accordance with those from Example 4,where polymer concentrations of 20% (w/w) or higher with respect to thepolymeric solution are able to control the initial risperidone diffusionand achieve prolonged release overtime.

Example 7: Study of Different Drug Loadings

The risperidone implantable formulation of this example was prepared bycompletely dissolving polymer Resomer® RG503 (RG503, 50:50lactic/glycolic acid, Boehringer Ingelheim) in DMSO and subsequentlydispersing the drug in the appropriate amount to obtain a final drugloading between 7-13% (w/w) (weight of risperidone in respect of thetotal composition weight).

Composition drug loading 7% 13% Ingredient Amount (mg) Risperidone  1515 Resomer ® RG503 (polymer)  60 30 DMSO 140 70In Vivo Plasma Levels after Intramuscular Administration to New ZealandRabbit

The risperidone formulation of this example was injected intramuscularlyinto New Zealand White rabbits weighing an average of 3 kg. The amountinjected corresponded to a dose of 15 mg risperidone and the compositionwas placed intramuscularly in the left hind leg using a syringe with a20G needle. Total number of rabbits was 3. After injection, plasmalevels were obtained at 0, 4 h, 1 d, 2 d, 3 d, 5 d, 7 d, 10 d, 14 d, 17d, 21 d, 24 d, 28 d, 31 d, 35 d, 38 d and 42 d.

The kinetics of the plasma levels corresponding to the risperidoneactive moiety was evaluated by measuring both risperidone and its activemetabolite 9-OH-risperidone in the plasma samples. The profile of therisperidone active moiety plasma levels is shown in FIG. 11. The resultsare expressed as the addition of the risperidone plus 9-OH-risperidoneconcentrations (ng/ml) as a function of time, since the therapeuticactivity of 9-OH-risperidone is substantially equivalent to that ofrisperidone. As depicted in the figure, the injection of an amount ofcomposition equivalent to 15 mg risperidone to New Zealand White rabbitsresulted in moderate and controlled initial plasma levels. An increasein the drug loading is related to a lower initial drug diffusion andrelease, producing as a result a decrease in the initial plasma levels.Therefore, a high drug loading is preferable for the case of long-termformulations, in order to achieve better balanced plasma levels in thewhole drug release period. In general terms, a preferred range for thedrug loading is between 4 and 16%, and a more preferred range is between7 and 13%, expressed as the weight percent of drug with respect to thetotal composition.

Example 8: Study of Different Particle Sizes

In the present example, the following compositions of implantableformulations according to the invention were tested:

Composition A:

Ingredient Amount (mg) Resomer ® RG503 (polymer) 100 Risperidone 25Dimethyl sulfoxide (solvent) 233.3

Composition B:

Ingredient Amount (mg) Resomer ® RG503 (polymer) 50 Risperidone 25Dimethyl sulfoxide (solvent) 116.7 RG503, 50:50 lactic/glycolic acidpolymer (Boehringer Ingelheim)

The risperidone-implantable formulations were prepared by completelydissolving the polymer in the solvent and subsequently suspending thedrug in said polymeric solution. The following different risperidoneparticle size distributions were evaluated for the same formulation:

-   -   25-350 microns: d0.1, 25 microns and d0.9, 350 microns (not more        than 10% of drug particles with a particle size smaller than 25        microns, and not more than 10% particles larger than 350        microns).    -   25-225 microns: d0.1 of 25 microns and d0.9 of 225 microns (not        more than 10% of drug particles with a particle size smaller        than 25 microns, and not more than 10% particles larger than 225        microns).    -   90-150 microns: sieved between 90-150 microns    -   45-90 microns: sieved between 45-90 microns    -   milled, <10 microns: drug milled to d0.9 10 microns (not more        than 10% particles larger than 10 microns).

In Vitro Release Profile:

The risperidone release from the formulations corresponding toComposition B was evaluated according to the following procedure: theamount of formulation corresponding to 25 mg of risperidone was injectedfrom prefilled syringes equipped with a 21G needle into flasks followedby the careful addition of a pre-warmed release medium. The releasemedium was 250 ml phosphate buffer, pH=7.4. The flasks were then placedinto an oven at 37° C. and kept under horizontal shaking at 50 rpm. Atpreviously scheduled time points (2 h, 1 d, and periodically up to amaximum of 35 d), 5 ml of release medium was collected and replaced withfresh buffer, and the amount of risperidone present in the sample wasdetermined by UV spectrophotometry.

The profile of risperidone released from the implants of this example isshown in FIG. 12. Results are expressed as % Risperidone released fromthe implants as a function of time. As depicted in FIG. 12, the smalldrug particles (less than 10 microns) favored the in vitro drugdiffusion during first days following administration of the implantableformulation, whereas the use of a mixture of particle sizes, comprisinglarger and smaller particles, reduced the initial diffusion.Accordingly, in some embodiments, the risperidone comprises a broadparticle size distribution, which can be monomodal, bimodal or trimodal.

In Vivo Plasma Levels after Intramuscular Administration to New ZealandRabbit

The risperidone formulations corresponding to Compositions A and B ofthis example were injected intramuscularly into New Zealand Whiterabbits weighing an average of 3 kg. The amount injected corresponded toa dose of 15 mg risperidone and the composition was placedintramuscularly in the left hind leg using a syringe equipped with a 20Gneedle. Total number of rabbits was 3. After injection, plasma levelswere obtained at 0, 4 h, 1 d, 2 d, 3 d, 5 d, 7 d, 10 d, 14 d, 17 d, 21d, 24 d, 28 d, 31 d, 35 d, 38 d and 42 d.

The kinetics of the plasma levels corresponding to the risperidoneactive moiety was evaluated by measuring both risperidone and its activemetabolite 9-OH-risperidone in the plasma samples. The profile of therisperidone active moiety plasma levels is shown in FIGS. 13 and 14 forCompositions A and B, respectively. The results are expressed as theaddition of the risperidone plus 9-OH-risperidone concentrations (ng/ml)as a function of time, since the therapeutic activity of9-OH-risperidone is substantially equivalent to that of risperidone. Asdepicted in the figures, the injection of an amount of formulation ofthe Compositions A and B corresponding to an equivalent to 15 mgrisperidone to New Zealand White rabbits resulted in moderate andcontrolled initial plasma levels followed by significant plasma levelsup to at least 21 days. The smaller particle sizes produce an initialraise in the plasma levels and shorten the therapeutic plasma levelswindow. The use of higher particle sizes, thus avoiding smaller ones,resulted in a dramatic reduction of the initial burst effect bydecreasing drug diffusion and subsequent delay in drug release until thepolymer matrix degrades. As depicted in FIG. 14, the use of a controlledmixture of drug particle sizes provided a more controlled initialrelease during the diffusion phase, followed by an increase in plasmalevels once the polymer degradation begins.

In Vivo Plasma Levels after Intramuscular Administration to Beagle Dog

The risperidone formulations of Composition B of this example wereintramuscularly injected to Beagle dogs weighing an average of 10 kg.The amount injected corresponded to a dose of 25 mg risperidone and thecomposition was intramuscularly placed in the left hind leg using asyringe with a 20G needle. Total number of dogs was 3. After injection,plasma levels were obtained at 0, 4 h, 1 d, 2 d, 3 d, 5 d, 7 d, 10 d, 14d, 17 d, 21 d, 24 d, 28 d, 31 d, 35 d, 38 d and 42 d.

The kinetics of the plasma levels corresponding to the risperidoneactive moiety was evaluated by measuring both risperidone and its activemetabolite 9-OH-risperidone in the plasma samples. The profile of therisperidone active moiety plasma levels is shown in FIG. 15. The resultsare expressed as the addition of the risperidone plus 9-OH-risperidoneconcentrations (ng/ml) as a function of time, since the therapeuticactivity of 9-OH-risperidone is substantially equivalent to that ofrisperidone.

The injection of risperidone formulations corresponding to Composition Bof this example in an amount equivalent to 25 mg risperidone to Beagledogs resulted in controlled initial plasma levels followed bysignificant plasma levels up to at least 28 days as it can be observedin FIG. 15. As previously noted in relation to the intramuscularadministration of Composition B to rabbits (FIGS. 13 and 14), theadministration of the same composition to dogs revealed the samevariable effect depending on drug particle size: Small particles (<10microns) induced higher initial plasma levels and a relatively fastdecrease in comparison with mixtures of particles sizes comprising bothsmall and large particles (25-225 microns), which combination is able toreduce the initial plasma levels and favors a more sustained plasmalevel along time.

Example 9: Study of the Viscosity of the Polymeric Solution

The risperidone-implantable formulations of this example were preparedby completely dissolving the polymer in DMSO or NMP as the solvent andsubsequently suspending the drug in said polymeric solution. Theformulations were the following in order to achieve polymeric solutionshaving different viscosities:

Polymer (%, w/w upon Viscosity of the Ingredient (mg) polymeric solutionpolymeric Risperidone Polymer (type) Solvent (type) (polymer + solvent))solution (Pa · s) 25 33.3 (Resomer ® RG503) 300 (DMSO) 10 0.03 15 60(Resomer ® RG752S) 140 (NMP) 30 0.10 25 66.5 (Resomer ® RG503 266.8(DMSO) 20 0.18 15 60 (Resomer ® RG752S) 90 (DMSO) 40 0.43 15 30(Resomer ® RG753S) 70 (DMSO) 30 0.66 15 60 (Resomer ® RG503) 140 (DMSO)30 1.12 15 60 Resomer ® RG503) 111.5 (DMSO) 35 2.73 15 60 (Resomer ®RG504) 140 (DMSO) 30 6.12 7.9 60 (Resomer ® RG503) 90 (DMSO) 40 6.77 2533.3 (Resomer ® RG503) 300 (DMSO) 10 RG7525, and RG7535, 75:25lactic/glycolic acid polymer (Boehringer Ingelheim) RG503 and RG504,50:50 lactic/glycolic acid polymer (Boehringer Ingelheim)

The above formulations can be otherwise expressed as follows.

Polymer Viscosity (% w/w with of the regard to polymeric polymer +solution Polymer Type solvent) (Pa · s) Resomer ® RG503 10 0.03Resomer ® RG752S 30 0.10 Resomer ® RG503 20 0.18 Resomer ® RG752S 400.43 Resomer ® RG753S 30 0.66 Resomer ® RG503 30 1.12 Resomer ® RG503 352.73 Resomer ® RG504 30 6.12 Resomer ® RG503 40 6.77

In Vitro Release Profile:

The risperidone release from the formulations was evaluated according tothe following procedure: the amount of formulation corresponding to 25mg of risperidone was injected from prefilled syringes equipped with a21G needle into flasks followed by the careful addition of a pre-warmedrelease medium. The release medium was 250 ml phosphate buffer, pH=7.4.The flasks were then placed into an oven at 37° C. and kept underhorizontal shaking at 50 rpm. At previously scheduled time points (2 h,1 d, and periodically up to a maximum of 42 d), 5 ml of release mediumwas collected and replaced with fresh buffer, and the amount ofrisperidone present in the sample was determined by UVspectrophotometry.

The profile of risperidone released from the implants of this example isshown in FIG. 16. Results are expressed as % Risperidone released fromthe implants as a function of time. As depicted in FIG. 16, the lowpolymer solution viscosities lead to completely uncontrollable (0.03Pa·s) and fast and high initial diffusion (0.18 Pa·s) of risperidone. Onthe other hand, polymer solution viscosities in the range 1.12-6.77 Pa·sresulted in well-controlled in vitro drug diffusion during first daysfollowing administration of the implantable formulation, followed bymoderate drug release rates up to 35-42 days.

In Vivo Plasma Levels after Intramuscular Administration to New ZealandRabbit

The risperidone compositions of this example were injectedintramuscularly to New Zealand White rabbits weighing an average of 3kg. The amount injected corresponded to a dose of 15 mg risperidone andthe composition was placed intramuscularly in the left hind leg using asyringe with a 20G needle. Total number of rabbits was 3. Afterinjection, plasma levels were obtained at 0, 4 h, 1 d, 2 d, 3 d, 5 d, 7d, 10 d, 14 d, 17 d, 21 d, 24 d, 28 d.

The kinetics of the plasma levels corresponding to the risperidoneactive moiety was evaluated by measuring both risperidone and its activemetabolite 9-OH-risperidone in the plasma samples. The profile of therisperidone active moiety plasma levels is shown in FIGS. 17, 18 and 19.The results are expressed as the addition of the risperidone plus9-OH-risperidone concentrations (ng/ml) as a function of time, since thetherapeutic activity of 9-OH-risperidone is substantially equivalent tothat of risperidone. As depicted in the figures, the injection of anamount of formulation corresponding to 15 mg risperidone to New ZealandWhite rabbits with compositions having a low viscosity (0.1 Pa·s) of thepolymeric solution resulted in high initial plasma levels but a fastdecrease of said levels. An intermediate polymer solution viscosity(0.43 Pa·s). still provided high initial plasma levels, although theirdecrease was more moderate than at lower viscosity. On the contrary,higher viscosity of the polymeric solutions resulted in controlledinitial plasma levels followed by significant plasma levels up at least21 days when viscosity is over 0.5 Pa·s. In general terms, a preferredrange for the viscosity of the polymer solution is between 0.5 and 7.0Pa·s, and a more preferred range between 0.7 and 2.0 Pa·s.

Example 10: Study of Different Drug/Polymer Mass Ratios

Risperidone implantable formulations were prepared by completelydissolving polymer Resomer® RG503 in the solvent and subsequentlydispersing the drug in the appropriate amounts to obtain the followingdrug/polymer mass ratios, expressed as the percentage of risperidoneweight in respect of the polymer+risperidone weight:

Risperidone/ Polymer mass ratio (Risperidone/ (Polymer + Ingredient (mg)Risperidone) Risperidone Polymer Solvent (% w/w)) 15 85 140 15.0 15 60140 20.0 15 45 83.5 25.0 15 35 83.5 30.0 15 30 70 33.3 15 27.8 67.8 35.015 25 100 37.5 25 33.3 300 42.9

The above formulations can be otherwise expressed as follows:

Risperidone/Polymer mass ratio (Risperidone/(Polymer + Risperidone) (%w/w)) 15.0 20.0 25.0 30.0 33.3 35.0 37.5 40.0

In Vitro Release Profile:

The risperidone release from some of the formulations of this examplewas evaluated according to the following procedure: the amount offormulation corresponding to 25 mg of risperidone was injected fromprefilled syringes equipped with a 21G needle into flasks followed bythe careful addition of a pre-warmed release medium. The release mediumwas 250 ml phosphate buffer, pH=7.4. The flasks were then placed into anoven at 37° C. and kept under horizontal shaking at 50 rpm. Atpreviously scheduled time points (2 h, 1 d, and periodically up to amaximum of 42 d), 5 ml of release medium was collected and replaced withfresh buffer, and the amount of risperidone present in the sample wasdetermined by UV spectrophotometry.

The profile of risperidone released from the formulations is shown inFIG. 20. The results are expressed as % Risperidone released from theformulation as a function of time. The range for the risperidone/polymerratio between 15-35% presented in this example shows acceptable in vitroinitial risperidone diffusion and a release time longer than 28 days. Onthe other hand, ratios of the order of 40% showed an inadequate controlof the in vitro drug release, probably because the amount of polymerpresent in the composition was not enough for the proper risperidoneentrapment into the matrix.

In Vivo Plasma Levels after Intramuscular Administration to New ZealandRabbit

Some of the risperidone compositions of this example were injectedintramuscularly to New Zealand White rabbits weighing an average of 3kg. The amount injected corresponded to a dose of 15 mg risperidone andthe composition was placed intramuscularly in the left hind leg using asyringe with a 20G needle. Total number of rabbits was 3. Afterinjection, plasma levels were obtained at 0, 4 h, 1 d, 2 d, 3 d, 5 d, 7d, 10 d, 14 d, 17 d, 21 d, 24 d, 28 d, 31 d, 35 d, 38 d and 42 d.

The kinetics of the plasma levels corresponding to the risperidoneactive moiety was evaluated by measuring both risperidone and its activemetabolite 9-OH-risperidone in the plasma samples. The profile of therisperidone active moiety plasma levels is shown in FIGS. 21 and 22. Theresults are expressed as the addition of the risperidone plus9-OH-risperidone concentrations (ng/ml) as a function of time, since thetherapeutic activity of 9-OH-risperidone is substantially equivalent tothat of risperidone. As depicted n the figures, the injection of anamount of formulation corresponding to 15 mg risperidone to New ZealandWhite rabbits resulted in all the cases presented in this example toshow plasma levels from the first day until at least day 24. However, insome cases, compositions resulted in moderate and well controlledinitial plasma followed by sustained levels during 24 days, there beingno high difference between that initial plasma levels (first day) andthe ones found on the next days. Whereas in other cases, thecompositions resulted in inadequately controlled initial plasma levels,showing high plasma levels during first day followed by a notablydecrease during next days until plasma levels were stabilized andmaintained until drug it is completely released. These finding resultedhighly surprising, since it was expected that the lower drug/polymermass ratio, the better control of the initial release due to a higherpresence of polymer to entrap and retain the drug. However, what wefound here, is that ratios lower than 25% could not elicit anappropriate risperidone release and showed a high diffusion from thecompositions during the initial term following administration. On theother hand, ratios in the interval 25-35% were capable of providing moresustained plasma levels since the very beginning of release with lowerdifferences between initial levels (first day) and following ones (nextdays). Finally, an increase in the ratio over 35% resulted in higherinitial plasma levels compared to ones obtained during the next days, sothat a value of 35% in this ratio is considered to represent a limit forthe minimum amount of polymer which is necessary to provide a goodrisperidone entrapment into the composition matrix. In general terms, apreferred range for the risperidone/polymer mass ratio is between 25 and35%. A most preferred value is around 33%.

In Vivo Plasma Levels after Intramuscular Administration to Beagle Dog

The risperidone formulations of this example corresponding todrug/polymer mass ratios of 20 and 33.3% were injected intramuscularlyto Beagle dogs weighing an average of 10 kg. The amount injectedcorresponded to a dose of 25 mg risperidone and the composition wasplaced intramuscularly in the left hind leg using a syringe with a 20Gneedle. Total number of dogs was 3. After injection, plasma levels wereobtained at 0, 4 h, 1 d, 2 d, 3 d, 5 d, 7 d, 10 d, 14 d, 17 d, 21 d, 24d, 28 d, 31 d, 35 d, 38 d and 42 d.

The kinetics of the plasma levels corresponding to the risperidoneactive moiety was evaluated by measuring both risperidone and its activemetabolite 9-OH-risperidone in the plasma samples. The profile of therisperidone active moiety plasma levels is shown in FIG. 23. The resultsare expressed as the addition of the risperidone plus 9-OH-risperidoneconcentrations (ng/ml) as a function of time, since the therapeuticactivity of 9-OH-risperidone is substantially equivalent to that ofrisperidone. As depicted in the figure, the injection of an amount offormulation corresponding to 25 mg risperidone to Beagle dogs resultedin well-controlled initial plasma levels with sustained levels up to atleast 35 days. As previously described for rabbits, a higherdrug/polymer mass ratio, between 25-35%, resulted in a surprisinglybetter control of the drug release than lower ones (below 25%), thusproviding a controlled initial diffusion followed by a more constantrelease, so that more balanced plasma levels are obtained.

Example 11: Study of Different Polymeric Solution/Drug Mass Ratios

The risperidone implantable formulations of this example were preparedby completely dissolving polymer Resomer® RG503 (RG503, 50:50lactic/glycolic acid, Boehringer Ingelheim) in dimethyl sulfoxide andsubsequently dispersing the drug in the mentioned polymeric solutionadjusted to different polymeric solution/risperidone mass ratios (w/w):6.7, 10, 11.4, 14 and 19, expressed as the weight percent of polymersolution with respect to drug.

Polymer solution/ Ingredient (mg) drug Risperidone Polymer Solvent massratio 15 114 171 19 15 70.5 140 14 15 60 111.5 11.4 15 60 90 10 15 30 706.7In Vivo Plasma Levels after Intramuscular Administration to New ZealandRabbit

The risperidone composition of this example was injected intramuscularlyto New Zealand White rabbits weighing an average of 3 kg. The amountinjected corresponded to a dose of 15 mg risperidone and the compositionwas placed intramuscularly in the left hind leg using a syringe with a20G needle. Total number of rabbits was 2. After injection, plasmalevels were obtained at 0, 4 h, 1 d, 2 d, 3 d, 5 d, 7 d, 10 d, 14 d, 17d, 21 d, 24 d, 28 d, 31 d, 35 d, 38 d and 42 d.

The kinetics of the plasma levels corresponding to the risperidoneactive moiety was evaluated by measuring both risperidone and its activemetabolite 9-OH-risperidone in the plasma samples. The profile of therisperidone active moiety plasma levels is shown in FIG. 24. The resultsare expressed as the addition of the risperidone plus 9-OH-risperidoneconcentrations (ng/ml) as a function of time, since the therapeuticactivity of 9-OH-risperidone is substantially equivalent to that ofrisperidone. As depicted in the figure, the injection of an amount offormulation corresponding to 15 mg risperidone to New Zealand Whiterabbits resulted in well-controlled initial plasma levels 4 hpost-administration, which plasma levels were maintained up to 28 daysin all polymeric solution/risperidone cases, although the lower thepolymeric solution/risperidone ratio, the more constant levels wereachieved. However the value of 19 is not considered adequate due tobeing capable to control the very initial release (and plasma levels)approximately during the first 24 h, but not during the following days(from day 2^(nd) to 5^(th)). Therefore, an appropriate compositionshould comprise a polymer solution/drug mass ratio below 15 and at leastuntil the last value tested, e.g. 4.

Example 12: Study of Different Solvent/Drug Ratios

Risperidone implantable formulations were prepared by completelydissolving polymer Resomer® RG503 (RG503, 50:50 lactic/glycolic acid,Boehringer Ingelheim) in dimethyl sulfoxide and subsequently dispersingthe drug in the mentioned polymeric solution adjusted to differentsolvent/risperidone ratios between 4.7 and 11.4 (w/w), expressed asweight percent of solvent with respect to drug.

Ingredient (mg) Solvent/ Risperidone Polymer Solvent drug ratio 15 114171 11.4 15 70.5 140 9.3 15 60 111.5 7.4 15 60 90 6 15 30 70 4.7In Vivo Plasma Levels after Intramuscular Administration to New ZealandRabbit

The risperidone compositions of this example were injectedintramuscularly to New Zealand White rabbits weighing an average of 3kg. The amount injected corresponded to a dose of 15 mg risperidone andthe composition was placed intramuscularly in the left hind leg using asyringe with a 20G needle. Total number of rabbits was 2. Afterinjection, plasma levels were obtained at 0, 4 h, 1 d, 2 d, 3 d, 5 d, 7d, 10 d, 14 d, 17 d, 21 d, 24 d, 28 d, 31 d, 35 d, 38 d and 42 d.

The kinetics of the plasma levels corresponding to the risperidoneactive moiety was evaluated by measuring both risperidone and its activemetabolite 9-OH-risperidone in the plasma samples. The profile of therisperidone active moiety plasma levels is shown in FIG. 25. The resultsare expressed as the addition of the risperidone plus 9-OH-risperidoneconcentrations (ng/ml) as a function of time, since the therapeuticactivity of 9-OH-risperidone is substantially equivalent to that ofrisperidone. As depicted in the figure, the injection of an amount offormulation corresponding to 15 mg risperidone to New Zealand Whiterabbits resulted in initial plasma levels 4 h post-administration, whichplasma levels were sustained up to 28 days in all solvent/risperidoneratios, although the lower the solvent/risperidone ratio, the moreconstant levels were achieved. All ratios studied provided an adequatecontrol of the initial plasma levels during first 24 h, however, theratio 11.4 is not considered adequate because it exhibits a lateruncontrolled drug diffusion/release during the following days (days2^(nd) to 5^(th)). Therefore it is consider that an appropriatesolvent/risperidone ratio should be lower than 10 and until at least thelowest value tested, e.g. 4.

Example 13: Study of the Addition of a pH Modifier

The same risperidone implantable formulations were prepared bycompletely dissolving the polymer in the solvent (DMSO) and subsequentlydispersing the drug in the mentioned polymeric solution with theoptional addition of an alkaline agent such magnesium hydroxide.

Amount (mg) No Alkaline Alkaline Ingredient agent agent Resomer ® RG503(polymer) 100 100 Risperidone 25 25 Dimethyl sulfoxide (solvent) 233.3233.3 Magnesium Hydroxide — 8.3 RG503, 50:50 lactic/glycolic acidpolymer (Boehringer Ingelheim)In Vivo Plasma Levels after Intramuscular Administration to New ZealandRabbit

The risperidone compositions of this example were injectedintramuscularly to New Zealand White rabbits weighing an average of 3kg. The amount injected corresponded to a dose of 15 mg risperidone andthe composition was placed intramuscularly in the left hind leg using asyringe with a 20G needle. Total number of rabbits was 2. Afterinjection, plasma levels were obtained at 0, 4 h, 1 d, 2 d, 3 d, 5 d, 7d, 10 d, 14 d, 17 d, 21 d, 24 d, 28 d, 31 d, 35 d, 38 d and 42 d.

The kinetics of the plasma levels corresponding to the risperidoneactive moiety was evaluated by measuring both risperidone and its activemetabolite 9-OH-risperidone in the plasma samples. The profile of therisperidone active moiety plasma levels is shown in FIG. 26. The resultsare expressed as the addition of the risperidone plus 9-OH-risperidoneconcentrations (ng/ml) as a function of time, since the therapeuticactivity of 9-OH-risperidone is substantially equivalent to that ofrisperidone. As depicted in the figure, the injection of an amount offormulation corresponding to 15 mg risperidone to New Zealand Whiterabbits resulted in initial plasma levels since 4 h post-administrationup to at least 23 days. However, by including an alkaline agent withinthe polymer matrix, a more sustained plasma levels starting from 4 hpost-administration and an increase in the time showing therapeuticrisperidone plasma levels, i.e. up to at least 32 days, was achieved.

Example 14: Study of Reconstitution of the Formulations

Risperidone implantable formulations were prepared with the followingcomposition:

Ingredient Amount (mg) Resomer ® RG503 (polymer) 50 Risperidone 25Dimethyl sulfoxide (solvent) 116.7 RG503, 50:50 lactic/glycolic acidpolymer (Boehringer Ingelheim)

The risperidone selected for the compositions of this example showed ausual particle size distribution between 25-225 microns (not more than10% of drug particles with a particle size smaller than 25 microns, andnot more than 10% larger than 225 microns). Three different methods wereapplied to reconstitute the composition:

A) Vial. The polymeric solution was prepared by weighing the appropriateamounts of polymer and solvent and mixing them by vortexing until thepolymer had completely dissolved in the solvent. Then, the appropriaterisperidone amount was added to the polymeric solution and a homogeneoussuspension was obtained by vortexing.

B) Syringes. The risperidone, the polymer and the solvent were weighedindependently in syringes. The polymeric solution was then prepared byconnecting the respective syringes by a fluid connector so that thesolvent was moved from the syringe containing it to the syringecontaining the polymer and then making several forward-backward cyclesfrom one syringe to the other by pushing the respective plungers. Oncethe polymer is completely dissolved in the solvent, the third syringecontaining the risperidone was connected and a homogeneous suspensionwas then obtained by doing several additional cycles.

C) Freeze-drying. Polymer and risperidone were freeze-dried in aprefilled syringe and the solvent was placed in a second syringe. Thesyringes were connected by a fluid connector and then the solvent wasmoved to the syringe containing the freeze-dried polymer-risperidonemixture and finally several forward-backward cycles were repeated untila homogeneous suspension was achieved.

Preparation methods B and C can also be carried out by direct connectionof syringes using female-male luer syringes.

In Vitro Release Profile:

The risperidone release from formulations corresponding to the threedifferent methods was evaluated according to the following procedure:the amount of formulation corresponding to 25 mg of risperidone wasinjected from prefilled syringes equipped with a 21G needle into flasksfollowed by the careful addition of a pre-warmed release medium. Therelease medium was 250 ml phosphate buffer pH=7.4. The flasks were thenplaced into an oven at 37° C. and kept under horizontal shaking at 50rpm. At previously scheduled time (2 h, 1 d, 3 d, 7 d, 10 d, 14 d, 17 d,21 d, 24 d, 28 d, 31 d and 35 d), 5 ml of release medium was collectedand replaced with fresh buffer, and the amount of risperidone amountpresent in the sample was determined by UV spectrophotometry.

The profile of risperidone released from the implants is shown in FIG.27. The results are expressed as % Risperidone released from theformulation as a function of time. As depicted in FIG. 27, the releaseprofile of the implantable formulations prepared by the three differentmethods was the same during first 2 weeks. However, after 14 days thepreparation Method A (vial) resulted in a slightly slower release rate,probably due the higher porosity of the implants formed by the other 2methods because of the air introduced to the formulation during thereconstitution process.

In Vivo Plasma Levels after Intramuscular Administration to New ZealandRabbit

The risperidone compositions of this example were injectedintramuscularly to New Zealand White rabbits weighing an average of 3kg. The amount injected corresponded to a dose of 15 mg risperidone andthe composition was placed intramuscularly in the left hind leg using asyringe with a 20G needle. Total number of rabbits was 2. Afterinjection, plasma levels were obtained at 0, 4 h, 1 d, 2 d, 3 d, 5 d, 7d, 10 d, 14 d, 17 d, 21 d, 24 d, 28 d, 31 d, 35 d, 38 d and 42 d.

The kinetics of the plasma levels corresponding to the risperidoneactive moiety was evaluated by measuring both risperidone and its activemetabolite 9-OH-risperidone in the plasma samples. The profile of therisperidone active moiety plasma levels is shown in FIG. 28. The resultsare expressed as the addition of the risperidone plus 9-OH-risperidoneconcentrations (ng/ml) as a function of time, since the therapeuticactivity of 9-OH-risperidone is substantially equivalent to that ofrisperidone. As depicted in the figure, the injection of an amount offormulation corresponding to 15 mg risperidone to New Zealand Whiterabbits resulted in initial plasma levels starting from 4 hpost-administration up to at least 28 days. The methods consist ofreconstitution of a formulation pre-filled in different containers bytheir mixing (Methods B and C) produced slightly higher initial plasmalevels. This could be due to the higher porosity, and consequentlyhigher initial diffusion, of the implantable formulations prepared bythese two methods in comparison with Method A (preparation inside avial). This fact could be also the reason for their higher plasma levelsduring the first week after administration.

In Vivo Plasma Levels after Intramuscular Administration to Beagle Dog

The risperidone formulations of this example were also injectedintramuscularly to Beagle dogs weighing an average of 10 kg. The amountinjected corresponded to a dose of 25 mg risperidone and the compositionwas placed intramuscularly in the left hind leg using a syringe with a20G needle. Total number of dogs was 3. After injection, plasma levelswere obtained at 0, 4 h, 1 d, 2 d, 3 d, 5 d, 7 d, 10 d, 14 d, 17 d, 21d, 24 d, 28 d, 31 d, 35 d, 38 d and 42 d.

The kinetics of the plasma levels corresponding to the risperidoneactive moiety was evaluated by measuring both risperidone and its activemetabolite 9-OH-risperidone in the plasma samples. The profile of therisperidone active moiety plasma levels is shown in FIG. 29. The resultsare expressed as the addition of the risperidone plus 9-OH-risperidoneconcentrations (ng/ml) as a function of time, since the therapeuticactivity of 9-OH-risperidone is substantially equivalent to that ofrisperidone. As it can be seen in the cited figure, the injection of anamount of formulation corresponding to 25 mg risperidone to Beagle dogsresulted in well-controlled initial plasma levels with sustained levelsup to at least 35 days using different preparation methods such as priorelaboration of polymeric solution followed by drug addition (vial,method A) or by direct reconstitution starting from solid components(syringes, method B).

Example 15: Study of the Effect of Sterilization by Beta-IrradiationProcess

In the present example, the composition of the risperidone implantableformulations was as follows maintaining always the same amounts of drug,polymer and solvent: Risperidone 15 mg, Polymer 30 mg and Solvent 70 mg.

Polymer Polymer Mean Polymer Irradi- lactic/ End Molecular SolutionCompo- ation glycolic Terminal weight Viscosity sition (KGy) ratio group(g/mol) (Pa.s) Solvent A 0 50:50 capped 27,020 1.62 DMSO B 10 50:50capped 23,189 1.30 DMSO C 15 50:50 capped 22,182 1.00 DMSO D 25 50:50capped 20,991 0.81 DMSO E 0 50:50 capped 39,708 5.97 DMSO F 25 50:50capped 27,891 1.78 DMSO

The implantable formulations were prepared by direct reconstitution of 2prefilled syringes, first one with polymer and risperidone mixture, andsecond one with the solvent. Syringes were connected.

Syringes containing polymer plus risperidone mixtures were sterilized by3-irradiation in the range 10-25 KGy. As indicated in the table, twodifferent polymers were tested, one is an end capped 50:50 polymer withmean Mw 27,020 g/mol, non-irradiated or irradiated at 10, 15 or 25 KGy,and the other an end capped 50:50 polymer with mean Mw 39,708 g/mol,non-irradiated or irradiated at 25 KGy.

Formulations A and E received sterilization irradiations that gave riseto different compositions due to different polymer molecular weightlosses during the process; however, the inherent viscosity did not fallbelow 0.25 dL/g in any case, and the viscosity of the polymer solutionremained in the range of about 0.5-7 Pa·s, which range previouslyestablished as being adequate for forming long lasting implantableformulations (Example 9), i.e. formulations exhibiting a release profilelast at least 14 days.

In Vitro Release Profile:

The risperidone release from compositions of this example was evaluatedaccording to the following procedure. The amount of formulationcorresponding to 25 mg of risperidone was injected from prefilledsyringes equipped with a 21G needle into flasks having a pre-warmedrelease medium. The release medium was 250 ml phosphate buffer, pH=7.4.The flasks were then placed into an oven at 37° C. and kept underhorizontal shaking at 50 rpm. At previously scheduled time points (2 h,1 d, and periodically up to 28 days) 5 ml of release medium wascollected and replaced with fresh buffer and the amount of risperidonepresent in the sample was determined by UV spectrophotometry. Theprofile of risperidone released from the implants of this example isshown in FIG. 30 and FIG. 31. The results are expressed as % drugreleased from implants as a function of time.

As depicted in FIG. 30, the release of risperidone from the sameformulation either non irradiated (composition A) or irradiated atdifferent levels (compositions B, C and D) in the range 10-25 KGyresulted in very similar profiles because polymer solution viscositieswere still within the preferred established range 0.7 to 2.0 Pa·s. FIG.31 shows how the other polymer with a higher Mw (39,708 g/mol)(composition E) which presents an slightly slower release profile, onceit is irradiated (composition F) presents a release profile closer tothe non-irradiated lower Mw polymer (composition A), due to the loss ofmolecular weight during sterilization process, which leads to acomposition with polymer solution viscosity key parameter withinpreferred ranges 0.7-2.0 Pa·s.

In Vivo Plasma Levels after Intramuscular Administration to New ZealandRabbit:

The risperidone compositions A, B, C, D and G of this example wereinjected intramuscularly to New Zealand White rabbits weighing anaverage of 3 kg. The amount injected corresponded to a dose of 15 mgrisperidone, and the composition was placed intramuscularly in the lefthind leg using a syringe with a 20G needle. Total number of rabbits percomposition was 3. After injection, plasma levels were obtained at 0, 4h, 1 d, 2 d, 5 d, 7 d, 10 d and periodically up to 28 days.

The kinetics of the plasma levels corresponding to the risperidoneactive moiety was evaluated by measuring both risperidone and its activemetabolite 9-OH-risperidone in the plasma samples. The profile of therisperidone active moiety plasma levels is shown in FIG. 32 and FIG. 33.The results are expressed as the addition of the risperidone plus9-OH-risperidone concentrations (ng/ml) as a function of time, since thetherapeutic activity of 9-OH-risperidone is substantially equivalent tothat of risperidone. As demonstrated in these figures, the injection ofan amount of composition equivalent to 15 mg risperidone to New ZealandWhite rabbits resulted in very similar plasma levels as could bepredicted since in vitro behavior was very similar after irradiation.FIG. 32 revealed not extraordinary changes in the risperidone activemoiety plasma levels when a formulation comprising a 27,020 g/mol meanmolecular weight polymer (composition A), was irradiated at 10, 15 or 25KGy (composition B, C and D, respectively) since key parameter such aspolymer solution viscosity is still inside the previously preferabledetermined range of 0.7 to 2.0 Pa·s.

A higher molecular weight polymer (39,708 g/mol), with polymer solutionviscosity out of the preferable range (5.97 Pa·s, composition E), uponirradiation at 25 KGy (since higher molecular weight polymers sufferproportionally higher molecular weight losses during irradiation) leadsto a polymer with lower inherent viscosity and consequently lower butstill adequate polymer solution viscosity of 1.78 Pa·s (composition F).That higher molecular weight polymer, after 25 KGy irradiation, resultedextremely close to the lower one without any irradiation (composition A)in both molecular weight and polymer solution viscosity, thereforefulfilling in this manner the polymer solution viscosity parameterleading to adequate long lasting implantable systems in line with thepresent invention, and experimenting a very similar in vivo behavior(plasma levels profile) as shows FIG. 33.

Comparative Example 2 (not According to the Invention)

Risperidone implantable formulations (Prodex 2 and Prodex 4C) wereprepared according to procedures described in U.S. Pat. No. 5,688,801.

In Vivo Plasma Levels after Intramuscular Administration to Beagle Dog

The risperidone formulations of this example were injectedintramuscularly to Beagle dogs weighing an average of 10 kg afterresuspension of microparticles in 2 ml of a 2.5% (in weight)carboxymethyl cellulose solution in water. The amount injectedcorresponded to a dose of 25 mg risperidone and the composition wasplaced intramuscularly in the left hind leg. Total number of dogs was 6.After injection, plasma levels were obtained at 0, 1 d, 2 d, 6 d, 9 d,13 d, 15 d, 17 d, 19 d, 21 d, 23 d, 26 d, 29 d, 33 d, 35 d, 42 d and 56d.

The kinetics of the plasma levels corresponding to the risperidoneactive moiety was evaluated by measuring both risperidone and its activemetabolite 9-OH-risperidone in the plasma samples. The profile of therisperidone active moiety plasma levels is shown in FIG. 34. The resultsare expressed as the addition of the risperidone plus 9-OH-risperidoneconcentrations (ng/ml) as a function of time, since the therapeuticactivity of 9-OH-risperidone is substantially equivalent to that ofrisperidone. As depicted in the figure, the results of this test showedthat the administration of risperidone in preformed microparticles,according to procedures described in the prior art, fails to providesignificant plasma levels of risperidone active moiety in dogs until thethird week following administration. The plasma levels observed amongthe 6 animals also showed a poor reproducibility, and the rise wastypically observed from approximately day 21^(st) until approximatelyday 28^(h) following administration, to then diminish at a similar rate,thereby providing a peak of plasma level with an approximate extensionof 2 weeks. These profiles are completely different to the profilesobserved in the examples according to the invention and clearlydemonstrates the difference between the plasma levels obtained with thecomposition according to the invention compared to those obtainedaccording to the prior art.

From the above experiments it can be concluded that the viscosity of thepolymeric solution (polymer+solvent), surprisingly shows a strongerinfluence on the control of the drug release than other various factorsthat could conceivably be considered as having a stronger effect, suchas the nature of the polymer or its concentration. This result isunexpected and surprising in the light of the prior art.

It can also be concluded that, when a certain portion of the polymer isremoved at a constant risperidone amount,—or, in other words, that thedrug/polymer mass ratio is increased-, the initial release is lower andconsequently the plasma level profiles are flattened. This effect islikewise surprising, since the presence of a lower amount of polymercould be a priori related to a lower capacity to retain the drug andproviding a worse initial release control.

The phrase “pharmaceutically acceptable” is employed herein to refer tothose compounds, materials, compositions, and/or dosage forms which are,within the scope of sound medical judgment, suitable for use in contactwith tissues of human beings and animals and without excessive toxicity,irritation, allergic response, or any other problem or complication,commensurate with a reasonable benefit/risk ratio.

In view of the above description and the examples below, one of ordinaryskill in the art will be able to practice the invention as claimedwithout undue experimentation. The foregoing will be better understoodwith reference to the following examples that detail certain proceduresfor the preparation of embodiments of the present invention. Allreferences made to these examples are for the purposes of illustration.The following examples should not be considered exhaustive, but merelyillustrative of only a few of the many embodiments contemplated by thepresent invention.

Additional Disclosure

The invention provides an injectable composition comprising:

-   -   a. a drug, such as risperidone and/or a metabolite (such as        paliperidone) and/or a prodrug thereof) having a water        solubility of less than or about 2 mg/ml;    -   b. a biocompatible polymer, which is a polymer or        copolymer-based on lactic acid or a copolymer of lactic acid and        glycolic acid having a monomer ratio of lactic to glycolic acid        in the range from 48:52 to 100:0, wherein the polymer (or        copolymer) has an inherent viscosity in the range of 0.20-0.50        dl/g; and    -   c. a water-miscible solvent having a dipole moment of about        3.7-4.5 D and a dielectric constant of between 30 and 50,        thereby providing the injectable composition having a viscosity        in the range of about 0.50 and 4.0 Pa·s.

Embodiments of the invention include those wherein: a) the drug isselected from the group consisting of risperidone and paliperidone; b)the solvent is DMSO; c) the polymer is selected from the groupconsisting of poly(lactic acid), poly(lactic acid-co-glycolic acid)copolymer and a combination thereof; d) the monomer ratio of thepoly(lactic acid-co-glycolic acid) copolymer is in the range of about48:52 to 100:0, and the copolymer has an inherent or intrinsic viscosityin the range of about 0.16-0.60 dl/g measured in chloroform at 25° C.and at a concentration of 0.1% wt; e) the polymer has an inherent orintrinsic viscosity in the range of about 0.20-0.50 dl/g or 0.25-0.48dl/g, measured in chloroform at 25° C. and 0.1% concentration wt/v; f)the concentration of polymer in the injectable composition is in therange of about 20 to about 50%, about 25 to about 40%, or about 30 toabout 40%, expressed as the percentage of polymer weight based on totalweight of injectable composition; g) the viscosity of the injectablecomposition is in the range of about 0.5-7.0 Pa·s, about 0.5-4.0 Pa·s,or about 0.7-4.0 Pa·s; h) the drug (or metabolite or prodrug thereof)has a particle size where not more than 10% of the total volume of theparticles is less than the range 0.1-10 μm, 0.5-10 μm or 1-10 μm, notmore than the 10% of the total volume of particles is greater than therange 225-1000 μm, 225-700 μm or 225-400 μm, respectively, and the d0.5of the size distribution is in the range of about 10-1000 μm, 20-700 μmor 40-200 μm, respectively, i) the ratio of solvent to polymer is in therange of about 4:1 to about 1:1, about 3:1 to about 1.2:1, or about 2:1to about 1.4:1; k) the composition is injectable by hand with a syringethrough a 18-22 gauge or 20-21 gauge needle; and/or 1) the polymericsolution excluding drug has a viscosity in the range of about 0.5 to 3.0Pa·s or 0.7 to 3.0 Pa·s.

Embodiments of the invention include those wherein: a) the drug issoluble, partially soluble or insoluble in the solvent; b) thesolubility of the drug in the solvent is about 90 mg/ml or less, about65 mg/ml or less, or about 10 mg/ml or less; c) a minor portion, a majorportion or none of the drug is present in particulate form in theinjectable composition; d) the particle size distribution of the drugexpressed as volume is as follows: d0.9 about 150-400 μm, d0.5 about40-200 μm and d0.1 about 10-60 μm; e) the mass ratio of solvent to drugis in the range of about 10:1 to about 1.5:1 f) the concentration ofdrug in the injectable composition is in the range of about 4% to about40% wt or about 4% to about 25%, expressed as the percentage of the drugwith respect to the total composition weight; g) the drug is present asparticles, is partially dissolved in or is completely dissolved in theinjectable composition prior to administration; h) the mass ratio of theamount of polymeric solution (polymer+solvent) to the amount of drug inthe injectable composition ranges from about 24:1 to about 1.5:1 orabout 15:1 to about 3:1.

Embodiments of the invention include those wherein: a) drug is presentin solid form in the container prior to mixing with the solvent; b) drugis present in particulate form or as a lyophilisate in the containerprior to mixing with the solvent; c) the kit further comprises analkaline agent; d) the mole ratio of alkaline agent to drug ranges from1/3 to 5/2; e) the solvent, polymeric solution, drug and/or injectablecomposition is sterilized prior to administration; and/or f) the kitfurther comprises an alkaline agent in either or both containers.

Another aspect of the invention provides a method for the treatment of adisease, disorder or condition that is therapeutically responsive to arisperidone or a metabolite thereof, the method comprising administeringan amount of injectable composition, as defined herein, to a subject inneed thereof, wherein the amount of injectable composition comprises adose of drug sufficient to continuously provide therapeuticallyeffective plasma levels of drug and/or metabolite in the subjectthroughout a dosing period of at least 14 days or at least four weeksbeginning from the day of administration.

As used herein and unless otherwise specified, the drug or activeingredient included in the injectable composition can be present in freebase, salt, amorphous, crystalline, anhydrous, hydrate, optically pure,optically enriched or racemic forms thereof. Combinations of thesevarious forms are also within the scope of the invention. A prodrug,metabolite or derivative of the drug can also be included.

The injectable composition comprises at least a polymer, a solvent and adrug, wherein the composition has a viscosity within a specified range,the polymer has an intrinsic viscosity within a specified range, thedrug has a water solubility at or below a maximum specified value, thepolymer has a specified composition.

The drug is preferably a poorly water-soluble drug with a watersolubility about 2 mg/ml or less at 20° C. The poorly water soluble drugmay be present in any form having the desired water solubility maximum.The advantage of this low solubility is that the initial burst of thedrug when the solvent diffuses into the external aqueous medium,following placement therein, is greatly reduced.

The initial release of drug from the implant can be controlled byvarying the drug/polymer mass ratio of the injectable composition. Insome embodiments, this mass ratio, expressed as the percentage of thedrug weight with respect to total weight of the drug plus polymer, is inthe range of about 15-50% weight, more preferably about 25-50% wt, andmost preferably about 33-45% wt.

Yet another factor that may contribute toward controlling the initialrelease of drug from the implant is the drug's particle size. Largeparticles provide a smaller surface area per weight thereby reducing theinitial release (burst) but the release may be then delayed until thebeginning of the degradation of the polymeric matrix. On the other hand,small particles evoke higher burst levels due to increased surface areaand easier drug diffusion from small particles during implant hardening,followed by continuous drug release levels due to the combination of theprocesses of drug diffusion and implant erosion. Consequently, in apreferred embodiment of the invention a wide particle size distribution,combining large and small particle sizes in different ratios, is used inorder to reduce the initial burst and still maintain a suitable constantdrug release by diffusion of smaller particles during the first phase ofrelease and gradual release of drug from the bigger particles while thepolymer degrades, i.e. during the period of time (days to weeks)following the initial burst phase.

The mass ratio of the amount of solvent to the amount of risperidone (mgsolvent/mg risperidone) in the injectable composition ranges may alsocontribute toward controlling the initial release of drug from theimplant. In some embodiments, the mass ratio of the amount of solventand the amount of drug (mg solvent/mg drug) in the injectablecomposition ranges from about 12:1 to about 1.5:1, about 10:1 to about1.5:1 or about 5:1 to about 1.5:1.

The polymer can be sterilized by 3-irradiation. The polymer andrisperidone were mixed and subjected to 3-irradiation in the range 10-25KGy. Exposure to radiation caused the polymer to degrade therebyresulting in a polymer with reduced molecular weight and a correspondingpolymer solution with reduced viscosity. In some embodiments, theinvention provides a process for preparing an injectable composition asdescribed herein, the process comprising: a) subjecting a PLGA polymerto a sufficient amount of 3-irradiation to degrade at least a portion ofthe polymer thereby reducing its molecular weight; and b) dissolving thepolymer in a solvent to form a polymeric solution having a desiredviscosity. In some embodiments, a mixture of drug and PLGA polymer areexposed to beta-irradiation prior to addition of the solvent, whichwould result in formation of a sterilized injectable composition of theinvention.

Embodiments of the invention include those wherein: a) the molecularweight of the polymer is greater before irradiation than it is afterirradiation; b) the molecular weight of the polymer is greater than 10KDa before irradiation; c) the molecular weight of the polymer is in therange of 10-60 KDa, 10-52 KDa or 10-43 KDa after irradiation; d) theviscosity of a polymeric solution containing polymer that has not beenirradiated is greater than about 0.5 Pa·s; e) the viscosity of apolymeric solution containing polymer that has been irradiated is in therange of 0.5-7.0 Pa·s, 0.5-3.0 Pa·s or 0.7 to 2.0 Pa·s.; and/or f) thesufficient amount of radiation is at least 10, at least 15, at least 20or at least 25 KGy.

A treatment period will vary according to the drug administered and thedisease, disorder or condition being treated and according to the dosageand administration protocols approved by the U.S.F.D.A. for each drug.For example, a first dose of injectable composition is administered anda second dose of injectable composition can be administered within oneto two weeks following administration of the first dose, such that eachdose will have its own corresponding dosing period, and the dosingperiods would overlap.

In humans, the average plasma concentration of risperidone can rangefrom about 3-200, about 5-80, or about 10-60 ng/ml when an amount ofinjectable composition equivalent to a dose of about 25-150, about37.5-125, or about 50-100 mg of risperidone is administered. The averageCmin during the dosing period is in the range of about 1-80, 5-50, orabout 5-40 ng/ml when an amount of injectable composition equivalent toa dose of about 25-150, about 37.5-125, or about 50-100 mg,respectively, of risperidone is administered. The average Cmax duringthe dosing period is in the range of about 8-300, 10-150, or 10-120ng/ml when an amount of injectable composition equivalent to a dose of25-150, 37.5-125, or 50-100 mg, respectively, of risperidone isadministered. Some individual subjects may, on an equivalent dose basis,exhibit plasma concentrations outside the ranges specified herein forreasons such as poor health, advanced age, compromised metabolism, renalfailure, disease, etc. Even so, a majority of subjects in a patientpopulation to which the injectable implant is administered will exhibitplasma concentrations with those specified herein.

As used herein, the term about is taken to mean ±10%, ±5% or ±1% of aspecified value.

The invention provides a method of treating a disease, disorder orcondition that is therapeutically responsive to risperidone ormetabolite thereof, the method comprising administering to a subject inneed thereof an amount of injectable depot composition sufficient toprovide a therapeutic dose of risperidone, to form an implant in thesubject, wherein the injectable depot composition consists ofrisperidone, and a polymeric solution of DMSO and PLGA copolymer, andwherein:

the content of risperidone is 13% wt±10%, based upon the weight of thecomposition, and the risperidone possesses a particle distributionselected from:

-   -   a. not more than 10% of the total volume of the particles is        smaller than 10 microns, not more than the 10% of the total        volume of particles is greater than 225 microns, and the d0.5 is        in the range of 10-200 microns;    -   b. not more than 10% of the total volume of the particles is        less than the range 1-10 μm, not more than the 10% of the total        volume of particles is greater than the range 225-400 μm, and        the d0.5 of the size distribution is in the range of about        40-200 μm; or    -   c. expressed as volume, d0.9 is about 150 to about 400 μm, d0.5        is about 40 to about 200 μm and d0.1 is about 10 to about 60 μm;        the mass ratio of DMSO to risperidone is 4.66±10%:1;        the mass ratio of polymeric solution to risperidone is about        6.66±10%:1;        the PLGA copolymer is an end-capped biodegradable        poly(lactide-co-glycolide) copolymer having a monomer ratio of        lactic acid to glycolic acid of 50:50 and an inherent viscosity        in the range of 0.20±10% dl/g to 0.50±10% dl/g as measured in        chloroform at 25° C. at a concentration of 0.1% wt/v with an        Ubbelohde size 0c glass capillary viscometer;        the polymeric solution has a viscosity in the range of 0.5-3.0        Pa·s; and        the amount of risperidone dissolved in the injectable        composition is ≤20% wt.

The invention provides an injectable depot composition consisting ofrisperidone, and a polymeric solution of DMSO and PLGA copolymer,wherein:

-   the content of risperidone is 13% wt±10%, based upon the weight of    the composition, and the risperidone possesses a particle    distribution selected from:    -   a. not more than 10% of the total volume of the particles is        smaller than 10 microns, not more than the 10% of the total        volume of particles is greater than 225 microns, and the d0.5 is        in the range of 10-200 microns;    -   b. not more than 10% of the total volume of the particles is        less than the range 1-10 microns, not more than the 10% of the        total volume of particles is greater than the range 225-400        microns, and the d0.5 of the size distribution is in the range        of about 40-200 microns; or    -   c. expressed as volume, d0.9 is about 150 to about 400 microns,        d0.5 is about 40 to about 200 microns and d0.1 is about 10 to        about 60 microns;        the mass ratio of DMSO to risperidone is 4.66±10%:1;        the mass ratio of polymeric solution to risperidone is about        6.66±10%:1;        the PLGA copolymer is an end-capped biodegradable        poly(lactide-co-glycolide) copolymer having a monomer ratio of        lactic acid to glycolic acid of 50:50 and an inherent viscosity        in the range of 0.20±10% dl/g to 0.50±10% dl/g as measured in        chloroform at 25° C. at a concentration of 0.1% wt/v with a        Ubbelohde size 0c glass capillary viscometer;        the polymeric solution has a viscosity in the range of 0.5-3.0        Pa·s; and        the amount of risperidone dissolved in the injectable        composition is 20% wt.

The invention provides an injectable depot composition consisting of:

-   drug, which is risperidone present as particles having a particle    size distribution as follows: not more than 10% of the total volume    of drug particles is less than 10 microns in size, not more than 10%    of the total volume of drug particles is greater than 225 microns in    size, and the d0.5 of the size distribution is in the range of about    60-130 microns; and-   polymeric solution consisting of: DMSO; and biocompatible    poly(lactide-co-glycolide) (PLGA) copolymer comprising lactic acid    and glycolic acid monomers, wherein the monomers are present at a    monomer ratio of lactic to glycolic acid of 48:52 to 52:48, the    copolymer has an inherent viscosity in the range of 0.25-0.48 dl/g    as measured in chloroform at 25° C. and at a concentration of 0.1%    wt/v with a Ubbelohde size 0c glass capillary viscometer; wherein    the polymeric solution has a viscosity in the range of about 0.7    Pa·s to about 3.0 Pa·s; and wherein    the drug content is about 13% wt with respect to the total    composition weight;    the DMSO to drug mass ratio is about 4:1 to 5:1;    the polymeric solution to drug mass ratio is about 6.5:1 to 7:1.

The invention also provides a method of treating a disease, disorder orcondition that is therapeutically responsive to a risperidone, e.g.schizophrenia or bipolar disorder, the method comprising administeringto a subject in need thereof an amount of injectable depot compositionto form an implant in the subject, wherein the amount is sufficientprovide a therapeutic dose of risperidone, whereby the implant providestherapeutic plasma levels of the risperidone from within 1 day afteradministration throughout a dosing period of at least two weeksfollowing administration thereof, wherein the injectable depotcomposition consists of:

-   risperidone present as particles having a particle size distribution    as follows: not more than 10% of the total volume of risperidone    particles is less than 10 microns in size, not more than 10% of the    total volume of risperidone particles is greater than 225 microns in    size, and the d0.5 of the size distribution is in the range of about    60-130 microns; and-   polymeric solution consisting of:    -   DMSO; and    -   biocompatible poly(lactide-co-glycolide) (PLGA) copolymer        comprising lactic acid and glycolic acid monomers, wherein the        monomers are present at a monomer ratio of lactic to glycolic        acid of 48:52 to 52:48, the copolymer has an inherent viscosity        in the range of 0.25-0.48 dl/g as measured in chloroform at        25° C. and at a concentration of 0.1% wt/v with an Ubbelohde        size 0c glass capillary viscometer; wherein        the polymeric solution has a viscosity in the range of about 0.7        Pa·s to about 3.0 Pa·s; and wherein        the risperidone content is about 13% wt with respect to the        total composition weight;        the DMSO to risperidone mass ratio is about 4:1 to 5:1; and        the polymeric solution to risperidone mass ratio is about 6.5:1        to 7:1.

The invention also provides a method of treating a disease, disorder orcondition that is therapeutically responsive to a risperidone, e.g.schizophrenia or bipolar disorder, the method comprising administeringto a subject in need thereof an amount of injectable depot compositionto form an implant in the subject, wherein the amount is sufficientprovide a therapeutic dose of risperidone, whereby the implant providestherapeutic plasma levels of the risperidone from within 1 day afteradministration throughout a dosing period of at least two weeksfollowing administration thereof, wherein the injectable depotcomposition consists of:

-   risperidone present as particles having a particle size distribution    as follows: not more than 10% of the total volume of risperidone    particles is less than 10 microns in size, not more than 10% of the    total volume of risperidone particles is greater than 225 microns in    size, and the d0.5 of the size distribution is in the range of about    60-130 microns; and-   polymeric solution consisting of:    -   DMSO; and    -   biocompatible poly(lactide-co-glycolide) (PLGA) copolymer        comprising lactic acid and glycolic acid monomers, wherein the        monomers are present at a monomer ratio of lactic to glycolic        acid of 48:52 to 52:48, the copolymer has an inherent viscosity        in the range of 0.25-0.48 dl/g as measured in chloroform at        25° C. and at a concentration of 0.1% wt/v with an Ubbelohde        size 0c glass capillary viscometer; wherein        the polymeric solution has a viscosity in the range of about 0.7        Pa·s to about 3.0 Pa·s;        the risperidone content is about 13% wt with respect to the        total composition weight;        the DMSO to risperidone mass ratio is about 4.66:1; and        the polymeric solution to risperidone mass ratio is about        6.66:1.

The invention also provides a method of treating schizophrenia orbipolar disorder comprising administering to a subject in need thereofan amount of injectable depot composition to form an implant in thesubject, wherein the amount is sufficient provide a therapeutic dose ofrisperidone, whereby the implant provides therapeutic plasma levels ofthe risperidone from within 1 day after administration throughout adosing period of at least two weeks following administration thereof,wherein the injectable depot composition consists of:

-   risperidone present as particles having a particle size distribution    as follows: not more than 10% of the total volume of risperidone    particles is less than 10 microns in size, not more than 10% of the    total volume of risperidone particles is greater than 225 microns in    size, and the d0.5 of the size distribution is in the range of about    60-130 microns; and-   polymeric solution consisting of:    -   DMSO; and    -   biocompatible poly(lactide-co-glycolide) (PLGA) copolymer        comprising lactic acid and glycolic acid monomers, wherein the        monomers are present at a monomer ratio of lactic to glycolic        acid of 48:52 to 52:48, the copolymer has an inherent viscosity        in the range of 0.25-0.48 dl/g as measured in chloroform at        25° C. and at a concentration of 0.1% wt/v with an Ubbelohde        size 0c glass capillary viscometer; wherein        the polymeric solution has a viscosity in the range of about 0.7        Pa·s to about 3.0 Pa·s; and wherein        the risperidone content is about 13% wt with respect to the        total composition weight;        the DMSO to risperidone mass ratio is about 4:1 to 5:1;        the polymeric solution to risperidone mass ratio is about 6.5:1        to 7:1;-   wherein the injectable composition provides a plasma profile for    risperidone and/or a metabolite thereof defined as follows

Dose (mg) Cmin (ng/ml) Cavg (ng/ml) Cmax (ng/ml) 25-150 1-80 3-200 8-300

-   during a dosing period of at least two weeks following    administration to a subject of an amount of the injectable    composition equivalent to the dose indicated;-   the injectable composition provides a substantially level plasma    concentration profile for risperidone and/or a metabolite thereof of    within ±20% of the average or mean plasma concentration during a    dosing period of at least 28 days following administration;-   the injectable composition releases at least 0.5% wt and no more    than 8% wt of its charge of risperidone within 24 hours after    administration; and-   prior to inclusion in the injectable composition, the copolymer has    been irradiated with about 10 KGy to about 25 KGy of beta-radiation.

1) A pharmaceutical kit for forming an extended release injectablesuspension, the kit comprising a) a mixture of PLGA copolymer and 25-150mg of risperidone in a first container; and b) DMSO in a secondcontainer; wherein the DMSO to risperidone mass ratio is about 4:1 to5:1; the mass ratio of risperidone to copolymer is about 25-35% wt,expressed as the percentage of the risperidone weight with respect tototal weight of risperidone plus copolymer; and the PLGA copolymer has amonomer ratio of lactic acid monomer to glycolic acid monomer of about50:50 to about 75:25. 2) The kit of claim 1, wherein the PLGA copolymera) is present as a freeze-dried solid; b) is ester end-capped; and/or c)is present as a 3-irradiated solid. 3) The kit of claim 1, wherein thefirst and second containers are independently selected from the groupconsisting of syringe, vial, and cartridge. 4) The kit of claim 3,wherein the syringes are connectable to each other. 5) The kit of claim4, wherein the syringes are directly connectable to each other. 6) Thekit of claim 5, wherein one syringe is a female luer syringe, and theother syringe is a male luer syringe. 7) The kit of claim 3, wherein thekit further comprises at least a 20-21 gauge needle. 8) The kit of claim1, wherein said extended release injectable suspension is formed bymixing the contents of the second container with the contents of thefirst container. 9) The kit of claim 8, wherein after intramuscularadministration to a human subject, the suspension forms an extendedrelease depot. 10) A pharmaceutical kit for forming an extended releaseinjectable suspension, the kit comprising a) a mixture of PLGA copolymerand 25-150 mg of particles of risperidone in a first syringe; and b)DMSO in a second syringe; wherein the DMSO to risperidone mass ratio isabout 4:1 to 5:1; the mass ratio of risperidone to copolymer is about25-35% wt, expressed as the percentage of the risperidone weight withrespect to total weight of risperidone plus copolymer; and the PLGAcopolymer has a monomer ratio of lactic acid monomer to glycolic acidmonomer of about 50:50 to about 75:25, and the PLGA copolymer is esterend-capped. 11) The kit of claim 10, wherein the mass ratio ofrisperidone to copolymer is about 33% wt, expressed as the percentage ofthe risperidone weight with respect to total weight of risperidone pluscopolymer. 12) The kit of claim 10, wherein the PLGA copolymer a) ispresent as a freeze-dried solid; and/or b) is present as a β-irradiatedsolid. 13) The kit of claim 10, wherein the syringes are connectable toeach other. 14) The kit of claim 13, wherein the syringes are directlyconnectable to each other. 15) The kit of claim 14, wherein one syringeis a female luer syringe and the other syringe is a male luer syringe.16) The kit of claim 10, wherein the kit further comprises at least a20-21 gauge needle. 17) The kit of claim 10, wherein said extendedrelease injectable suspension is formed by mixing the contents of thesecond container with the contents of the first container. 18) The kitof claim 10, wherein after intramuscular administration to a humansubject, the suspension forms an extended release depot. 19) Apharmaceutical kit for forming an extended release injectablesuspension, the kit comprising a) a mixture of PLGA copolymer and about50-100 mg of particles of risperidone in a first syringe; and b) DMSO ina second syringe; wherein one syringe is a female luer syringe, and theother syringe is a male luer syringe; the DMSO to risperidone mass ratiois 4.66±10%:1; the mass ratio of risperidone to copolymer is about 33%wt, expressed as the percentage of the risperidone weight with respectto total weight of risperidone plus copolymer; and the PLGA copolymerhas a monomer ratio of lactic acid monomer to glycolic acid monomer ofabout 50:50 to about 75:25, is ester end-capped, and is present as aβ-irradiated solid. 20) The kit of claim 19, wherein the kit furthercomprises a 20-21 gauge needle. 21) The kit of claim 19, wherein saidextended release injectable suspension is formed by mixing the contentsof the second syringe with the contents of the first syringe. 22) Thekit of claim 21, wherein after intramuscular administration to a humansubject, the suspension forms an extended release depot.